Oxime derivative and preparations thereof

ABSTRACT

The problem of the present invention is to provide a useful compound as a glucokinase activating agent, which is the oxime derivative of the formula [I]: 
                         
wherein Ring A is aryl or heteroaryl;
         Q is cycloalkyl, heterocycle, alkyl or alkenyl;   Ring T is heteroaryl or heterocycle;   R 1  and R 2  are independently hydrogen atom, halogen atom, cycloalkylsulfonyl or the like;   R 3  and R 4  are independently hydrogen atom, hydroxy, oxo, halogen atom or the like;   R 5  is hydrogen atom, halogen atom, cyano, nitro, tetrazolyl or the like;
 
or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel oxime derivative having anexcellent glucokinase activation effect, which is useful as a medicine.

BACKGROUND ART

Glucokinase (GK) is one of four hexokinases found in mammalian animals.The hexokinases catalyze a conversion of glucose intoglucose-6-phosphate which is the first step of glucose metabolism. GK islocalized mainly in hepatic parenchymal cells and pancreatic β cells,and plays an important role in whole body glucose homeostasis as arate-controlling enzyme for glucose metabolism in these cells. Thehepatic and pancreatic forms of the enzyme are different in N-terminal15 amino-acid sequence depending on the difference of each splicing, butare functionally indistinguishable.

Three hexokinases except GK are saturated in enzymatic activity at aglucose concentration below 1 mM, but Km of GK is 8 mM, which is withina physiological range of blood-glucose levels. Therefore, GK-mediatedintracellular glucose metabolism is activated as the concentration ofblood-glucose increases from normal level (5 mM) to postprandial level(10 to 15 mM).

A hypothesis that GK functions as a glucose sensor of pancreatic β cellsand hepatocyte has been proposed (nonpatent document 1).

Thereafter, it has been clarified that GK actually plays a definitelyimportant role in whole body glucose homeostasis according to theresults of GK genetically modified animal studies. GK KO mice die soonafter birth (nonpatent document 2), while both normal and diabetic miceoverexpressing GK showed lower glucose level than wild type animals(nonpatent document 3).

In maturity-onset diabetes of the young type II (MODY-2), which is oneof the genetically determined diabetes, loss of function mutations inthe GK has been found and it is thought that the low GK activity inMODY-2 results in hyperglycemia (nonpatent document 4). On the otherhand, families having a GK mutation with increased enzymatic activityhave been found and these people show hypoglycemia (nonpatent document5). Accordingly, GK is believed to be a glucose sensor and to play animportant role in maintenance of glucose homeostasis in human as well.It is expected that a GK activating compound has an insulinotropicaction in β cells, an enhancing effect of glucose uptake in liver andinhibitory effect of hepatic output since such a compound activates a GKsensor system, and hence, it is believed that such a compound is usefulfor treating, for example, Type 2 diabetes.

Recently, it has been shown that a pancreatic β cell type glucokinase isdistributed locally in feeding center (Ventromedial hypothalamus, VMH)in rat brain. About 20% of nerve cells in VMH are referred to as glucoseresponsive neurons and it has been thought from the past that they playimportant roles in controlling of body weights. An intracerebraladministration of glucose in rat decreases food intake, but on thecontrary, rat becomes overeating by an intracerebral administration of aglucose analog glucosamine, which cause the suppression of glucosemetabolism. In electrophysiological experiments, glucose responsiveneurons in VMH are stimulated when glucose increases from 5 to 20 mM,and the activity is blocked by glucosamine or the like (nonpatentdocument: Diabetes. 1999 September; 48(9): 1763-72). It is thought thata glucose sensor mechanism of VHM is similar to that of pancreatic βcells. Therefore, a GK activating substance has a possibility ofameliorating obesity which is one of the major problems in Type 2diabetes as well as correcting hyperglycemia.

Accordingly, a compound having a GK activation effect is useful as atreating and/or preventing agent of diabetes, or chronic complication ofdiabetes such as retinopathy, nephropathy, neuropathy, ischemic heartdisease or arteriosclerosis, or even obesity.

A compound having a GK activation effect includes, for example,pyridinecarboxylic acid derivatives (patent document 1),2-pyridine-carboxamide derivatives (patent document 2),heteroarylcarbamoyl-benzene derivatives (patent document 3), heteroarylderivatives (patent document 4), substituted arylcyclopropylacetamidederivatives (patent document 5), 5-substituted pyrazine or pyridinederivatives (patent document 6), substituted (thiazol-2-yl)amide orsulfonamide derivatives (patent document 7), substituted phenylacetamidederivatives (patent document 8) or amide derivatives (patent document9).

A method for preparing a 5-substituted 2-aminothiazole, which is anintermediate for the oxime derivative of the present invention, has beendescribed in patent documents 10 and 11, wherein5-fluoro-2-aminothiazole hydrochloride is prepared by treating5-bromo-2-trifluoroacetyl aminothiazole derived from5-bromo-2-aminothiazole hydrochloride with n-butyllithium, followed bytreating the resultant with N-fluorobenzenesulfonylimide (patentdocument 10, Preparation 61; patent document 11, Preparation 21). It isalso described in patent document 12 that 5-formyl-2-aminothiazolehydrobromide is prepared by a reaction of bromomalonaldehyde withthiourea. However, the methods disclosed in patent document 10 andpatent document 11 give the product in low yield and are notadvantageous as an industrial method. Additionally, the method disclosedin patent document 12 gives 2-aminothiazole as a by-product which isdifficult to remove, and hence it is difficult to obtain the desiredcompound in a high purity. Besides, said method can not be applied topreparations of wide range of 5-substituted 2-fluoro aminothiazolesother than 5-formyl-2-aminothiazole.

Compounds having an oxime structure therein have been described inpatent documents 13 to 16 and nonpatent documents 6 to 8.

[patent document 1] WO05/044801

[patent document 2] WO04/081001

[patent document 3] WO04/076420

[patent document 4] WO04/063194

[patent document 5] WO04/063179

[patent document 6] WO04/052869

[patent document 7] WO04/050645

[patent document 8] WO03/095438

[patent document 9] WO03/055482

[patent document 10] WO04/072031

[patent document 11] WO04/072066

[patent document 12] U.S. Pat. No. 4,225,719

[patent document 13] WO05/023761

[patent document 14] WO01/012189

[patent document 15] WO00/026202

[patent document 16] WO96/023763

[nonpatent document 1] American Journal Physiology, volume 247 (3Pt2)1984, p 527-536

[nonpatent document 2] Cell, volume 83, 1995, p 69-78

[nonpatent document 3] Proceedings of the National Academy of Sciencesof the U.S.A., volume 93, 1996, p 7225-7230

[nonpatent document 4] Nature Genetics, volume 356, 1992, p 721-722

[nonpatent document 5] New England Journal of Medicine, volume 338,1998, p 226-230

[nonpatent document 6] Bulletin des Societes Chimiques Belges (1994),103(5-6), 213-18

[nonpatent document 7] Bulletin of the Chemical Society of Japan (1993),66(8), 2335-8

[nonpatent document 8] Pharmazie (1988), 43(8), 535-6

DISCLOSURE OF INVENTION

The present invention provides a novel glucokinase activator, which isfor the prophylaxis and/or treatment of diseases involving glucokinase,such as diabetes, complication associated with diabetes, or obesity.

The present invention also provides a novel compound having an excellentglucokinase activation effect which is useful as an active ingredient ofa medicine.

According to extensive studies for problems to be solved by the presentinventions, it has been found that an oxime derivative of the followingformula has an excellent glucokinase activation effect, and the presentinvention has been completed.

The present invention includes the following embodiments.

-   (1) An oxime derivative of the general formula [I]:

wherein Ring A is aryl or heteroaryl;

Q is cycloalkyl, heterocycle, alkyl or alkenyl;

Ring T is heteroaryl or heterocycle;

R¹ is hydrogen atom, halogen atom, cycloalkylsulfonyl, alkylsulfonyl,alkylsulfinyl, alkylthio, or substituted or unsubstituted tetrazolyl;

R² is hydrogen atom, halogen atom, cycloalkylsulfonyl, substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted alkylthio,nitro, substituted or unsubstituted amino, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted heterocyclyl-thio,substituted or unsubstituted heterocyclyl-sulfinyl, substituted orunsubstituted heterocyclyl-sulfonyl, substituted or unsubstitutedheteroarylsulfonyl, alkenyloxy, substituted or unsubstituted alkoxy,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedheteroaryl, or substituted or unsubstituted heteroarylthio;

R³ and R⁴ are independently hydrogen atom, alkoxy, substituted orunsubstituted heterocycle, substituted or unsubstituted heteroaryl,alkoxyalkoxy, substituted or unsubstituted cycloalkyl, cyano,substituted or unsubstituted aryl, substituted or unsubstitutedcarbamoyl, hydroxy, alkanoyl, alkylthio, alkoxycarbonyl, substituted orunsubstituted aryloxy, halogen atom, oxo, or substituted orunsubstituted arylcarbonyloxy;

R⁵ is hydrogen atom, formyl, halogen atom, oxo, substituted orunsubstituted alkoxy, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted alkylthio, cyano, substituted orunsubstituted heterocyclyl-sulfonyl, nitro, substituted or unsubstitutedcycloalkyl, alkoxycarbonyl, alkenyl, alkylsulfonyl, substituted orunsubstituted carbamoyl, substituted or unsubstituted heteroarylthio,substituted or unsubstituted amino, carboxyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkynyl,substituted or unsubstituted heterocyclyl-carbonyl, substituted orunsubstituted heterocyclyl-oxy, substituted or unsubstitutedheterocycle, substituted or unsubstituted heterocyclyl-thio, substitutedor unsubstituted cycloalkyloxy, alkanoyl, or substituted orunsubstituted alkyl;

R⁶ is hydrogen atom, substituted or unsubstituted alkyl, halogen atom,or carboxyl;

or a pharmaceutically acceptable salt thereof.

-   (2) The oxime derivative of (1) wherein Ring A is aryl or    heteroaryl, provided that Ring A is not thiazolyl or thiadiazolyl,    or a pharmaceutically acceptable salt thereof.-   (3) The oxime derivative of (1) wherein Ring A is aryl, or a    pharmaceutically acceptable salt thereof.-   (4) The oxime derivative of (1) wherein Ring A is phenyl or pyridyl,    or a pharmaceutically acceptable salt thereof.-   (5) The oxime derivative of any one of (1) to (4) wherein Q is    cycloalkyl, heterocycle or alkyl, or a pharmaceutically acceptable    salt thereof.-   (6) The oxime derivative of any one of (1) to (4) wherein Q is    cycloalkyl or heterocycle, or a pharmaceutically acceptable salt    thereof.-   (7) The oxime derivative of any one of (1) to (4) wherein Q is    heterocycle, or a pharmaceutically acceptable salt thereof.-   (8) The oxime derivative of any one of (1) to (4) wherein Q is    tetrahydrofuryl group, or a pharmaceutically acceptable salt    thereof.-   (9) The oxime derivative of any one of (1) to (8) wherein Ring T is    heteroaryl or heterocycle of

or a pharmaceutically acceptable salt thereof.

-   (10) The oxime derivative of any one of (1) to (8) wherein Ring T is    heteroaryl of

or a pharmaceutically acceptable salt thereof.

-   (11) The oxime derivative of any one of (1) to (8) wherein Ring T is    thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl,    quinolyl, thiadiazolyl, pyrazolyl, thiazolopyrazinyl,    thiazolopyrimidinyl, cyclohexanothiazolyl or    dihydrothiazolopyridinyl, or a pharmaceutically acceptable salt    thereof.-   (12) The oxime derivative of any one of (1) to (8) wherein Ring T is    thiazolyl, thiazolopyridinyl, pyridyl, pyrazinyl, benzothiazolyl,    thiadiazolyl, thiazolopyrazinyl, thiazolopyrimidinyl,    cyclohexanothiazolyl or dihydrothiazolopyridinyl, or a    pharmaceutically acceptable salt thereof.-   (13) The oxime derivative of any one of (1) to (8) wherein Ring T is    thiazolyl, thiazolopyridinyl, pyrazinyl, thiadiazolyl,    thiazolopyrazinyl or thiazolopyrimidinyl, or a pharmaceutically    acceptable salt thereof.-   (14) The oxime derivative of any one of (1) to (8) wherein Ring T is    thiazolyl or thiazolopyridinyl, or a pharmaceutically acceptable    salt thereof.-   (15) The oxime derivative of any one of (1) to (14) wherein R¹ is    hydrogen atom or halogen atom, or a pharmaceutically acceptable salt    thereof.-   (16) The oxime derivative of any one of (1) to (14) wherein R¹ is    hydrogen atom, or a pharmaceutically acceptable salt thereof.-   (17) The oxime derivative of any one of (1) to (16) wherein R² is    cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl,    substituted or unsubstituted alkylthio, nitro, substituted or    unsubstituted amino, substituted or unsubstituted aminosulfonyl,    substituted or unsubstituted heterocyclyl-thio, substituted or    unsubstituted heterocyclyl-sulfonyl, substituted or unsubstituted    alkylsulfinyl, substituted or unsubstituted heteroarylsulfonyl,    substituted or unsubstituted heteroarylthio, or substituted or    unsubstituted heteroaryl, or a pharmaceutically acceptable salt    thereof.-   (18) The oxime derivative of any one of (1) to (16) wherein R² is    cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl,    substituted or unsubstituted aminosulfonyl, or substituted or    unsubstituted heterocyclyl-sulfonyl, or a pharmaceutically    acceptable salt thereof.-   (19) The oxime derivative of any one of (1) to (16) wherein R² is    cycloalkylsulfonyl, substituted or unsubstituted alkylsulfonyl, or    substituted or unsubstituted aminosulfonyl, or a pharmaceutically    acceptable salt thereof.-   (20) The oxime derivative of any one of (1) to (16) wherein R² is    cycloalkylsulfonyl, substituted or unsubstituted aminosulfonyl,    substituted or unsubstituted heterocyclyl-sulfonyl, or substituted    or unsubstituted heteroarylsulfonyl, or a pharmaceutically    acceptable salt thereof.-   (21) The oxime derivative of any one of (1) to (16) wherein R² is    cycloalkylsulfonyl, or a pharmaceutically acceptable salt thereof.-   (22) The oxime derivative of any one of (1) to (20) wherein the    substituent of the “substituted aminosulfonyl” in R² is substituted    or unsubstituted alkyl, cycloalkyl, substituted or unsubstituted    heterocycle, or alkoxy, or a pharmaceutically acceptable salt    thereof.-   (23) The oxime derivative of any one of (1) to (19) wherein the    substituent of the “substituted alkylsulfonyl” in R² is alkoxy, or a    pharmaceutically acceptable salt thereof.-   (24) The oxime derivative of any one of (1) to (23) wherein R³ and    R⁴ are independently hydrogen atom, alkoxy, substituted or    unsubstituted heterocycle, substituted or unsubstituted heteroaryl,    substituted or unsubstituted cycloalkyl, substituted or    unsubstituted aryl, substituted or unsubstituted carbamoyl, hydroxy,    alkanoyl, alkylthio, substituted or unsubstituted aryloxy, halogen    atom, oxo, or substituted or unsubstituted arylcarbonyloxy, or a    pharmaceutically acceptable salt thereof.-   (25) The oxime derivative of any one of (1) to (23) wherein R³ and    R⁴ are independently hydrogen atom, alkoxy, substituted or    unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,    or hydroxy, or a pharmaceutically acceptable salt thereof.-   (26) The oxime derivative of any one of (1) to (4) and (9) to (23)    wherein the group of -Q(R³)(R⁴) is cycloalkyl substituted with one    or two groups selected from alkoxy and hydroxy, heterocycle, or    alkyl substituted with 1 to 2 groups selected from hydroxy and    substituted or unsubstituted heteroaryl, or a pharmaceutically    acceptable salt thereof.-   (27) The oxime derivative of any one of (1) to (26) wherein when Q    is cycloalkyl, alkyl or alkenyl, then R³ and R⁴ are not any    combination of two groups independently selected from hydrogen,    alkoxy, cyano, substituted or unsubstituted aryl, hydroxy,    alkylthio, alkoxycarbonyl, or halogen atom, or a pharmaceutically    acceptable salt thereof.-   (28) The oxime derivative of any one of (1) to (4) and (9) to (23)    wherein Q is heterocycle and both of R³ and R⁴ are hydrogen atom, or    a pharmaceutically acceptable salt thereof.-   (29) The oxime derivative of any one of (1) to (28) wherein R⁵ is    hydrogen atom, formyl, halogen atom, oxo, substituted or    unsubstituted alkoxy, substituted or unsubstituted aminosulfonyl,    substituted or unsubstituted alkylthio, cyano, substituted or    unsubstituted heterocyclyl-sulfonyl, nitro, substituted or    unsubstituted cycloalkyl, alkoxycarbonyl, alkenyl, alkanoyl,    substituted or unsubstituted carbamoyl, substituted or unsubstituted    heteroarylthio, substituted or unsubstituted amino, substituted or    unsubstituted heteroaryl, substituted or unsubstituted alkynyl,    substituted or unsubstituted heterocyclyl-oxy, or substituted or    unsubstituted alkyl, or a pharmaceutically acceptable salt thereof.-   (30) The oxime derivative of any one of (1) to (28) wherein R⁵ is    hydrogen atom, halogen atom, substituted or unsubstituted alkoxy,    substituted or unsubstituted alkylthio, cyano, substituted or    unsubstituted cycloalkyl, alkanoyl, substituted or unsubstituted    carbamoyl, substituted or unsubstituted amino, substituted or    unsubstituted heterocyclyl-oxy, or substituted or unsubstituted    alkyl, or a pharmaceutically acceptable salt thereof.-   (31) The oxime derivative of any one of (1) to (28) wherein R⁵ is    halogen atom, substituted or unsubstituted alkoxy, substituted or    unsubstituted alkylthio, substituted or unsubstituted amino,    substituted or unsubstituted heterocyclyl-oxy, or substituted or    unsubstituted alkyl, or a pharmaceutically acceptable salt thereof.-   (32) The oxime derivative of any one of (1) to (28) wherein R⁵ is    substituted or unsubstituted alkoxy, substituted or unsubstituted    amino, substituted or unsubstituted heterocyclyl-oxy, or substituted    or unsubstituted alkyl, or a pharmaceutically acceptable salt    thereof.-   (33) The oxime derivative of any one of (1) to (32) wherein the    substituent of the “substituted alkyl” in R⁵ is substituted or    unsubstituted heterocycle, substituted or unsubstituted amino,    substituted or unsubstituted alkoxy, substituted or unsubstituted    carbamoyl, hydroxy, trialkylsilyloxy, alkylthio, alkylsulfonyl,    substituted or unsubstituted heterocyclyl-oxy, heteroaryl,    substituted or unsubstituted hydroxyimino, halogen atom, carboxyl,    alkoxycarbonyl, or alkanoyloxy, or a pharmaceutically acceptable    salt thereof.-   (34) The oxime derivative of any one of (1) to (33) wherein R⁶ is    hydrogen atom, or substituted or unsubstituted alkyl, or a    pharmaceutically acceptable salt thereof.-   (35) The oxime derivative of any one of (1) to (33) wherein R⁶ is    hydrogen atom, or a pharmaceutically acceptable salt thereof.-   (36) A pharmaceutical composition comprising a compound of any one    of (1) to (35) or a pharmaceutically acceptable salt thereof as an    active ingredient.-   (37) A method for preventing or treating diabetes, or complication    associated with diabetes including retinopathy, nephropathy,    neuropathy, ischemic heart disease or arteriosclerosis, or obesity,    which comprises administering an effective dose of a compound of any    one of (1) to (35) or a pharmaceutically acceptable salt thereof.-   (38) Use of a compound of any one of (1) to (35) or a    pharmaceutically acceptable salt thereof in the manufacture of a    medicament for treating or preventing diabetes, or complication    associated with diabetes including retinopathy, nephropathy,    neuropathy, ischemic heart disease or arteriosclerosis, or obesity.

The substituents on the group of each symbol in the compound [I] mean asdefined below.

In R¹-R⁶ of the compound [I], substituents in “substituted amino”,“substituted aminosulfonyl”, “substituted aminoalkyl”, “substitutedaminoalkanoyl”, “substituted carbamoyl”, “substituted carbamoylalkyl”,“substituted alkyl”, “substituted alkylthio”, “substitutedalkylsulfinyl”, “substituted alkylsulfonyl”, “substituted alkoxy”,“substituted alkanoyl”, “substituted alkynyl”, “substituted cycloalkyl”,“substituted cycloalkyloxy”, “substituted cycloalkylcarbonyl”,“substituted cycloalkylsulfonyl”, “substituted aryl”, “substitutedaryloxy”, “substituted arylcarbonyl”, “substituted arylcarbonyloxy”,“substituted arylsulfonyl”, “substituted arylalkylcarbonyl”,“substituted heteroaryl”, “substituted heteroarylthio”, “substitutedheteroarylsulfonyl”, “substituted heteroarylalkyl”, “substitutedheterocycle”, “substituted heterocyclyl-oxy”, “substitutedheterocyclyl-carbonyl”, “substituted heterocyclyl-thio”, “substitutedheterocyclyl-sulfinyl”, “substituted heterocyclyl-sulfonyl”,“substituted hydroxyimino”, and “substituted phenyl”, “substitutedpyridyl”, “substituted thiazolopyridinyl”, “substituted pyrazinyl”,“substituted pyrazolyl”, “substituted imidazolyl”, “substitutedthiazolyl”, “substituted benzothiazolyl”, “substituted quinolyl”,“substituted thiadiazolyl”, “substituted pyrazolyl”, “substitutedthiazolopyrazinyl”, “substituted thiazolopyrimidinyl”, “substitutedcyclohexanothiazolyl”, “substituted dihydro-thiazolopyridinyl”,“substituted triazolyl”, “substituted pyrimidinyl”, “substitutedpyrrolidinyl”, “substituted tetrahydrofuryl”, “substitutedthiacyclohexyl”, “substituted cyclopentyl”, “substituted piperazinyl”,“substituted piperazinylsulfonyl”, “substituted homopiperazinyl”,“substituted piperidinyl”, “substituted morpholinyl”, “substitutedthiomorpholinyl” “substituted perhydrodiazepinyl”, and “substitutedtetrazolyl” include those specifically indicated in EXAMPLES. Suchsubstituents include (1) alkyl being optionally substituted withhydroxy, alkoxy, amino, mono- or di-alkylamino, carbamoyl,tetrahydrofuryl or pyridyl, (2) cycloalkyl, (3) hydroxy, (4) alkoxy, (5)cyano, (6) halogen atom, (7) mono- or di-alkylamino, (8) amino beingoptionally substituted with alkanoyl, alkoxyalkanoyl or alkoxycarbonyl,(9) pyridyl, (10) carboxyl, (11) formyl, (12) alkanoyl being optionallysubstituted with mono- or di-alkylamino, hydroxy, alkoxy or alkanoyloxy,(13) cycloalkylcarbonyl, (14) alkoxycarbonyl, (15) oxo, (16)alkylsulfonyl, or the like. The R¹-R⁶ groups may have the same ordifferent 1 to 3 substituents selected from the above groups.

Additionally, each substituent is explained depending on each symbol (A,Q, T, R¹-R⁶) of the compound [I]. The groups of those symbols may havethe same or different 1 to 3 substitutents selected from the groups asdefined below.

A preferable substituent of substituted tetrazolyl in R¹ includes alkyl.

A preferable substituent of substituted alkylsulfonyl in R² includesalkoxycarbonyl, alkoxy, cycloalkyl (preferably, cyclopropyl), hydroxy,substituted or unsubstituted amino (substituent(s): 1 or 2 groupsselected from alkyl, alkanoyl), substituted or unsubstituted heteroaryl(preferably, imidazolyl, triazolyl) (substituent(s): alkyl),alkylsulfonyl, cyano, substituted or unsubstituted heterocycle(preferably, tetrahydrofuryl, tetrahydropyranyl, dihydro-3H-isoindolyl)(substituent(s): oxo, dioxo). More preferable one among them is alkoxy,cycloalkyl (preferably, cyclopropyl), hydroxy, particularly preferableone is alkoxy.

A preferable substituent of substituted alkylthio in R² includes alkoxy,cycloalkyl, alkoxycarbonyl, hydroxy, cyano, alkylthio, substituted orunsubstituted heterocycle (preferably, tetrahydrofuryl,tetrahydropyranyl, dihydro-3H-isoindolyl) (substituent(s): oxo, dioxo),heteroaryl (preferably, pyridyl). More preferable one among them isalkoxy, cycloalkyl, alkoxycarbonyl, hydroxy, cyano, alkylthio,heteroaryl (preferably, pyridyl).

A preferable substituent of substituted amino in R² includesheteroarylcarbonyl (preferably, pyridylcarbonyl), heteroarylalkanoyl(thienylalkanoyl), cycloalkylcarbonyl, cycloalkylsulfonyl,alkoxy-carbonylcarbonyl, heteroarylsulfonyl, alkylsulfonyl. Morepreferable one among them is alkoxycarbonylcarbonyl, alkylsulfonyl.

A preferable substituent of the substituted alkyl which is thesubstituent of substituted aminosulfonyl in R² includes amino beingoptionally substituted with mono- or di-alkyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; hydroxy; alkoxy;heteroaryl being optionally substituted with alkyl; cycloalkyl;alkoxycarbonyl; hydroxyalkoxy; heterocycle being optionally substitutedwith alkyl; halogen; alkylthio. More preferable one among them is aminobeing optionally substituted with mono- or di-alkyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; hydroxy; alkoxy;cycloalkyl; alkoxycarbonyl; heterocycle being optionally substitutedwith alkyl; halogen atom; particularly hydroxy, alkoxy.

A preferable substituent of the substituted heterocycle which is asubstituent of substituted aminosulfonyl in R² includes alkyl.

A preferable substituent of substituted heterocyclyl-thio in R² includeshydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl being optionallysubstituted with mono- or di-alkyl; heteroaryl; aminosulfonyl beingoptionally substituted with mono- or di-alkyl; amino being optionallysubstituted with mono- or di-alkyl; alkylsulfonyl; alkoxy; alkoxyalkyl.More preferable one among them is hydroxy; alkyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; oxo; alkoxy; alkoxyalkyl;particularly alkyl.

A preferable substituent of substituted heterocyclyl-sulfinyl in R²includes hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; heteroaryl; aminosulfonylbeing optionally substituted with mono- or di-alkyl; amino beingoptionally substituted with mono- or di-alkyl; alkylsulfonyl; alkoxy;alkoxyalkyl. More preferable one among them is hydroxy; alkyl; carbamoylbeing optionally substituted with mono- or di-alkyl; oxo; alkoxy;alkoxyalkyl; particularly alkyl.

A preferable substituent of substituted heterocyclyl-sulfonyl in R²includes hydroxy; alkyl; oxo; alkanoyl; hydroxyalkyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; heteroaryl; aminosulfonylbeing optionally substituted with mono- or di-alkyl; amino beingoptionally substituted with mono- or di-alkyl; alkylsulfonyl; alkoxy;alkoxyalkyl. More preferable one among them is hydroxy; alkyl; carbamoylbeing optionally substituted with mono- or di-alkyl; oxo; alkoxy;alkoxyalkyl.

A preferable substituent of substituted heteroarylsulfonyl in R²includes alkyl.

A preferable substituent of substituted alkoxy in R² includescycloalkyl.

A preferable substituent of substituted alkylsulfinyl in R² includesalkoxycarbonyl, alkoxy, alkoxyalkyl, cycloalkyl (preferably,cyclopropyl), hydroxy, substituted or unsubstituted amino(substituent(s): 1 or 2 groups selected from alkyl, alkanoyl),substituted or unsubstituted heteroaryl (preferably, imidazolyl,triazolyl) (substituent(s): alkyl), alkylsulfonyl, cyano, substituted orunsubstituted heterocycle (preferably, tetrahydrofuryl,tetrahydropyranyl, dihydro-3H-isoindolyl) (substituent(s): oxo, dioxo).More preferable one among them is alkoxy, cycloalkyl (preferably,cyclopropyl), hydroxy, particularly hydroxy.

A preferable substituent of substituted heteroaryl in R² includes alkyl.

A preferable substituent of substituted heterocycle in R³ and R⁴includes alkoxycarbonyl, oxo, alkyl, alkanoyl.

A preferable substituent of substituted heteroaryl in R³ and R⁴ includesalkyl; amino being optionally substituted with mono- or di-alkyl. Morepreferable one among them is alkyl.

A preferable substituent of substituted cycloalkyl in R³ and R⁴ includesbenzoyloxy, oxo, hydroxy, alkanoyl. More preferable one among them isoxo, hydroxy.

A preferable substituent of substituted aryl in R³ and R⁴ includesalkyl, cyano, halogen atom, alkoxy.

A preferable substituent of substituted carbamoyl in R³ and R⁴ includesalkyl.

A preferable substituent of substituted aryloxy in R³ and R⁴ includesalkyl, cyano, halogen atom, alkoxy.

A preferable substituent of substituted arylcarbonyloxy in R³ and R⁴includes alkyl, cyano, halogen atom, alkoxy.

A preferable substituent of substituted alkoxy in R⁵ includessubstituted or unsubstituted amino (substituent(s): 1 or 2 groupsselected from alkyl, alkoxycarbonyl); alkoxycarbonyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; carboxyl; hydroxy;substituted or unsubstituted heterocycle (substituent(s): oxo);trialkylsilyloxy; alkoxy. More preferable one is amino being optionallysubstituted with mono- or di-alkyl; carbamoyl being optionallysubstituted with mono- or di-alkyl; hydroxy; particularly amino beingoptionally substituted with mono- or di-alkyl; hydroxy.

A preferable substituent of substituted aminosulfonyl in R⁵ includesalkyl. Therefore, said substituent is mono-alkyl or di-alkyl, preferablydi-alkyl.

A preferable substituent of substituted alkylthio in R⁵ includes aminobeing optionally substituted with mono- or di-alkyl;alkoxycarbonylamino; halogen atom; hydroxy; carboxyl; carbamoyl beingoptionally substituted with mono- or di-alkyl; alkoxycarbonyl. Morepreferable one among them is amino being optionally substituted withmono- or di-alkyl; alkoxycarbonylamino; hydroxy; carbamoyl beingoptionally substituted with mono- or di-alkyl; particularlydialkylcarbamoyl.

A preferable substituent of substituted heterocyclyl-sulfonyl in R⁵includes alkyl.

A preferable substituent of substituted cycloalkyl in R⁵ includes aminobeing optionally substituted with mono- or di-alkyl.

A preferable substituent of substituted cycloalkyloxy in R⁵ includesamino being optionally substituted with mono- or di-alkyl.

A preferable substituent of substituted carbamoyl in R⁵ includessubstituted or unsubstituted alkyl (substituent(s): 1 or 2 groupsselected from hydroxy; cycloalkyl; heterocycle; amino being optionallysubstituted with mono- or di-alkyl; heteroaryl), cycloalkyl, heteroaryl.More preferable one among them is substituted or unsubstituted alkyl(substituent(s): 1 or 2 groups selected from hydroxy, heterocycle,dialkylamino, heteroaryl), cycloalkyl.

A preferable substituent of substituted heteroarylthio in R⁵ includesalkyl.

A preferable substituent of substituted amino in R⁵ includes alkyl,substituted or unsubstituted aminoalkyl (substituent(s): 1 or 2 groupsselected from alkyl, alkanoyl), alkanoyl, hydroxyalkyl, alkoxycarbonyl.More preferable one among them is alkyl, and hence, mono-alkyl ordi-alkyl, particularly di-alkyl.

A preferable substituent of substituted heteroaryl in R⁵ includes alkyl.

A preferable substituent of substituted alkynyl in R⁵ includes hydroxy,amino being optionally substituted with mono- or di-alkyl. Morepreferable one among them is hydroxy, dialkylamino.

A preferable substituent of substituted heterocyclyl-carbonyl in R⁵includes hydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. More preferableone among them is hydroxy, alkyl, hydroxyalkyl.

A preferable substituent of substituted heterocyclyl-oxy in R⁵ includeshydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. More preferable one amongthem is alkyl, oxo.

A preferable substituent of substituted heterocycle in R⁵ includeshydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. More preferable one amongthem is oxo.

A preferable substituent of substituted heterocyclyl-thio in R⁵ includeshydroxy, alkyl, oxo, hydroxyalkyl, alkanoyl. More preferable one isalkyl, alkanoyl.

A preferable substituent of substituted alkyl in R⁵ includes substitutedor unsubstituted heterocycle, substituted or unsubstituted amino,substituted or unsubstituted alkoxy, substituted or unsubstitutedcarbamoyl, hydroxy, trialkylsilyloxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted heterocyclyl-oxy, heteroaryl,substituted or unsubstituted hydroxyimino, halogen atom, more preferablysubstituted or unsubstituted heterocycle, substituted or unsubstitutedamino, substituted or unsubstituted alkoxy, hydroxy, substituted orunsubstituted alkylthio, substituted or unsubstituted heterocyclyl-oxy,substituted or unsubstituted hydroxyimino, halogen atom, furtherpreferably substituted or unsubstituted heterocycle, substituted orunsubstituted alkoxy, substituted or unsubstituted heterocyclyl-oxy,particularly substituted or unsubstituted heterocycle, substituted orunsubstituted alkoxy, further particularly substituted or unsubstitutedheterocycle.

A preferable substituent of substituted heterocycle which is thesubstituent of substituted alkyl in R⁵ includes alkyl; oxo;alkoxyalkanoyl; alkanoyl; alkoxy; alkanoylamino;cycloalkyl-carbonylamino; tri(halogeno)alkanoylamino; formylamino;alkoxy-carbonylamino; hydroxy; cycloalkylcarbonyl; tri(halogeno)alkyl;alkoxycarbonyl; formyl; amino being optionally substituted with mono- ordi-alkyl; aminosulfonyl being optionally substituted with mono- ordi-alkyl; alkylsulfonyl; heteroaryl; alkoxycarbonylalkyl;alkanoyloxyalkanoyl; alkoxycarbonylcarbonyl; aminoalkanoyl beingoptionally substituted with mono- or di-alkyl; substituted orunsubstituted carbamoyl (substituent(s): 1 or 2 groups selected fromalkyl, alkoxy); hydroxyalkanoyl; di(halogeno)alkanoyl; substituted orunsubstituted heterocyclyl-carbonyl (substituent(s): oxo); substitutedor unsubstituted hydroxyimino (substituent(s): alkoxycarbonyl);carboxyl; hydroxyalkoxy; alkoxyalkoxy; halogen atom; alkanoyloxy. Morepreferable one among them is alkyl; oxo; alkoxyalkanoyl; alkanoyl;alkoxy; alkanoylamino; cycloalkylcarbonylamino;tri(halogeno)alkanoylamino; formylamino; alkoxycarbonylamino;cycloalkylcarbonyl; tri(halogeno)alkyl; alkoxycarbonyl; formyl; aminobeing optionally substituted with mono- or di-alkyl; aminosulfonyl beingoptionally substituted with mono- or di-alkyl; alkylsulfonyl;heteroaryl; alkoxycarbonylalkyl; alkanoyloxyalkanoyl;alkoxycarbonylcarbonyl; aminoalkanoyl being optionally substituted withmono- or di-alkyl; carbamoyl being optionally substituted with mono- ordi-alkyl; hydroxyalkanoyl; di(halogeno)alkanoyl; substituted orunsubstituted heterocyclyl-carbonyl (substituent(s): oxo); substitutedor unsubstituted hydroxyimino (substituent(s): alkoxycarbonyl); morepreferably alkyl; oxo; alkoxyalkanoyl; alkanoyl; formyl; amino beingoptionally substituted with mono- or di-alkyl; alkylsulfonyl;alkanoyloxyalkanoyl; aminoalkanoyl being optionally substituted withmono- or di-alkyl; hydroxyalkanoyl; more preferably alkyl, alkanoyl,formyl, hydroxyalkanoyl, particularly alkyl, alkanoyl.

A preferable substituent of the substituted amino which is thesubstituent of substituted alkyl in R⁵ includes alkyl; carbamoylalkylbeing optionally substituted with mono- or di-alkyl; substituted orunsubstituted aminoalkyl (substituent(s): 1 or 2 groups selected fromalkyl, alkanoyl); alkoxyalkyl; hydroxyalkyl; alkoxyalkanoyl; heteroaryl;heteroarylalkyl. More preferable one among them is alkyl; carbamoylalkylbeing optionally substituted with mono- or di-alkyl; aminoalkyl beingoptionally substituted with mono- or di-alkyl; alkoxyalkyl; heteroaryl;particularly alkyl.

A preferable substituent of the substituted alkoxy which is thesubstituent of substituted alkyl in R⁵ includes hydroxy, alkoxy.

A preferable substituent of the substituted carbamoyl which is thesubstituent of substituted alkyl in R⁵ includes alkyl, alkoxy.

A preferable substituent of the substituted heterocyclyl-oxy which isthe substituent of substituted alkyl in R⁵ includes alkanoyl, alkyl,formyl, cycloalkylcarbonyl, alkoxyalkanoyl, alkylsulfonyl. Morepreferable one among them is alkanoyl, alkyl, particularly alkanoyl.

A preferable substituent of the substituted hydroxyimino which is thesubstituent of substituted alkyl in R⁵ includes alkoxycarbonyl.

Among the compounds [I] of the present invention, an example ofpreferable compounds are those in which R⁵ is substituted orunsubstituted alkyl.

Among the compounds [I], other preferable compounds are those of formula[I-A] as shown below, and the present invention includes also thefollowing embodiments:

-   (1) An oxime derivative of the general formula [I-A]:

wherein Ring A is aryl or heteroaryl;

Q is cycloalkyl, heterocycle, alkyl or alkenyl;

Ring T is heteroaryl or heterocycle;

R¹ and R² are independently hydrogen atom, halogen atom,cycloalkylsulfonyl, alkylsulfonyl, alkylsulfinyl, alkylthio, orsubstituted or unsubstituted tetrazolyl;

R³ and R⁴ are independently hydrogen atom, hydroxy, oxo, halogen atom,cyano, alkylthio, alkoxy, alkanoyl, alkoxyalkoxy, alkoxycarbonyl,substituted or unsubstituted carbamoyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocycle, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted aryloxy;

R⁵ is hydrogen atom, halogen atom, cyano, nitro, tetrazolyl, oxo,cycloalkyl, alkenyl, alkylthio, alkylsulfonyl, alkoxy, formyl, alkanoyl,alkoxycarbonyl, substituted or unsubstituted carbamoyl, substituted orunsubstituted aminosulfonyl, substituted or unsubstitutedheterocyclyl-carbonyl, substituted or unsubstitutedheterocyclyl-sulfonyl, or substituted or unsubstituted alkyl; or apharmaceutically acceptable salt thereof.

-   (2) The oxime derivative of (1) wherein Ring A is phenyl or pyridyl,    or a pharmaceutically acceptable salt thereof.-   (3) The oxime derivative of (1) wherein Ring A is phenyl, or a    pharmaceutically acceptable salt thereof.-   (4) The oxime derivative of any one of (1) to (3) wherein Q is    cycloalkyl, tetrahydrofuryl, alkyl or alkenyl, or a pharmaceutically    acceptable salt thereof.-   (5) The oxime derivative of any one of (1) to (3) wherein Q is    tetrahydrofuryl, or a pharmaceutically acceptable salt thereof.-   (6) The oxime derivative of any one of (1) to (3) wherein Q is    (3R)-3-tetrahydrofuryl, or a pharmaceutically acceptable salt    thereof.-   (7) The oxime derivative of any one of (1) to (6) wherein Ring T is    thiazolyl, pyrazinyl, thiadiazolyl, thiazolopyridinyl,    benzothiazolyl, cyclohexanothiazolyl or dihydrothiazolopyridinyl, or    a pharmaceutically acceptable salt thereof.-   (8) The oxime derivative of any one of (1) to (6) wherein Ring T is    thiazolyl, or a pharmaceutically acceptable salt thereof.-   (9) The oxime derivative of any one of (1) to (6) wherein Ring T is    2-thiazolyl, or a pharmaceutically acceptable salt thereof.-   (10) The oxime derivative of any one of (1) to (9) wherein one of R¹    and R² is hydrogen atom and the other is cycloalkylsulfonyl,    alkylsulfonyl, alkylsulfinyl, alkylthio, or substituted or    unsubstituted tetrazolyl, or a pharmaceutically acceptable salt    thereof.-   (11) The oxime derivative of any one of (1) to (9) wherein one of R¹    and R² is hydrogen atom and the other is cycloalkylsulfonyl, or a    pharmaceutically acceptable salt thereof.-   (12) The oxime derivative of (11) wherein Ring A is phenyl and the    cycloalkylsulfonyl is substituted to the 4-position of the phenyl,    or a pharmaceutically acceptable salt thereof.-   (13) The oxime derivative of any one of (1) to (12) wherein R³ and    R⁴ are independently hydrogen atom, hydroxy, alkoxy, substituted or    unsubstituted aryl, substituted or unsubstituted heteroaryl,    substituted or unsubstituted heterocycle, or substituted or    unsubstituted cycloalkyl, or a pharmaceutically acceptable salt    thereof.-   (14) The oxime derivative of any one of (1) to (12) wherein R³ and    R⁴ are independently hydrogen atom, hydroxy, alkoxy, substituted or    unsubstituted phenyl, substituted or unsubstituted pyrazolyl,    substituted or unsubstituted imidazolyl, substituted or    unsubstituted thiazolyl, substituted or unsubstituted triazolyl,    substituted or unsubstituted pyridyl, substituted or unsubstituted    pyrimidinyl, substituted or unsubstituted pyrrolidinyl, substituted    or unsubstituted thiacyclohexyl, or substituted or unsubstituted    cyclopentyl, or a pharmaceutically acceptable salt thereof.-   (15) The oxime derivative of any one of (1) to (12) wherein both of    R³ and R⁴ are hydrogen atom, or a pharmaceutically acceptable salt    thereof.-   (16) The oxime derivative of any one of (1) to (15) wherein R⁵ is    hydrogen atom, halogen atom, cyano, oxo, alkenyl, alkylthio, formyl,    alkanoyl, substituted or unsubstituted carbamoyl, substituted or    unsubstituted aminosulfonyl, substituted or unsubstituted    heterocyclyl-sulfonyl, or substituted or unsubstituted alkyl, or a    pharmaceutically acceptable salt thereof.-   (17) The oxime derivative of any one of (1) to (16) wherein a    substituent of the substituted alkyl in R⁵ is 1 to 3 substituents    selected from substituted or unsubstituted amino, substituted or    unsubstituted hydroxyimino, hydroxy, alkoxy, halogen atom, carboxyl,    alkoxycarbonyl, substituted or unsubstituted carbamoyl, alkanoyloxy,    and substituted or unsubstituted heterocycle, or a pharmaceutically    acceptable salt thereof.-   (18) The oxime derivative of any one of (1) to (15) wherein R⁵ is    hydrogen atom, halogen atom, cyano, oxo, alkenyl, alkylthio, formyl,    alkanoyl, substituted or unsubstituted carbamoyl, substituted or    unsubstituted aminosulfonyl, substituted or unsubstituted    piperazinylsulfonyl, or alkyl, or alkyl substituted with 1 to 3    groups selected from substituted or unsubstituted amino, substituted    or unsubstituted hydroxyimino, hydroxy, alkoxy, halogen atom,    alkoxycarbonyl, substituted or unsubstituted piperazinyl,    substituted or unsubstituted homopiperazinyl, substituted or    unsubstituted piperidinyl, substituted or unsubstituted morpholinyl    and substituted or unsubstituted thiomorpholinyl, or a    pharmaceutically acceptable salt thereof.-   (19) The oxime derivative of any one of (1) to (15) wherein R⁵ is    fluorine atom, or alkyl substituted with 1 to 3 groups selected from    substituted or unsubstituted piperazinyl, substituted or    unsubstituted morpholinyl and substituted or unsubstituted    thiomorpholinyl, or a pharmaceutically acceptable salt thereof.-   (20) The oxime derivative of any one of (1) to (15) wherein R⁵ is    fluorine atom, or alkyl substituted with piperazinyl being    optionally substituted with 1 to 3 substituents selected from alkyl,    oxo, alkanoyl and alkoxyalkanoyl, or a pharmaceutically acceptable    salt thereof.-   (21) The oxime derivative of any one of (1) to (15) wherein R⁵ is    fluorine atom, or piperazinylmethyl being optionally substituted    with alkyl or oxo on the carbon or being optionally substituted with    alkyl, alkanoyl or alkoxyalkanoyl on the nitrogen, or a    pharmaceutically acceptable salt thereof.-   (22) A medicine comprising as an active ingredient the oxime    derivative of any one of (1) to (21) or a pharmaceutically    acceptable salt thereof.-   (23) A glucokinase activating agent comprising as an active    ingredient the oxime derivative of any one of (1) to (21) or a    pharmaceutically acceptable salt thereof as an active ingredient.

The substituents on the group of each symbol of the compound [I-A] meansas defined below.

A substituent on the substituted alkyl in R⁵ includes substituted orunsubstituted amino, substituted or unsubstituted hydroxyimino, hydroxy,alkoxy, halogen atom, carboxyl, alkoxycarbonyl, substituted orunsubstituted carbamoyl, alkanoyloxy, substituted or unsubstitutedheterocycle, preferably substituted or unsubstituted amino, substitutedor unsubstituted hydroxyimino, hydroxy, alkoxy, halogen atom,alkoxycarbonyl, substituted or unsubstituted piperazinyl, substituted orunsubstituted homopiperazinyl, substituted or unsubstituted piperidinyl,substituted or unsubstituted morpholinyl, substituted or unsubstitutedthiomorpholinyl, or the like. The alkyl is substituted with the same ordifferent 1 to 3 substituents selected from the above groups.

In the compound [I-A], substituents in “substituted aryl”, “substitutedaryloxy”, “substituted heteroaryl”, “substituted heterocycle”,“substituted heterocyclyl-carbonyl”, “substitutedheterocyclyl-sulfonyl”, “substituted cycloalkyl”, “substituted phenyl”,“substituted pyrazolyl”, “substituted imidazolyl”, “substitutedthiazolyl”, “substituted triazolyl”, “substituted pyridyl”, “substitutedpyrimidinyl”, “substituted pyrrolidinyl”, “substituted thiacyclohexyl”,“substituted cyclopentyl”, “substituted piperazinyl”, “substitutedpiperazinylsulfonyl”, “substituted homopiperazinyl”, “substitutedpiperidinyl”, “substituted morpholinyl”, “substituted thiomorpholinyl”,“substituted tetrazolyl”, “substituted carbamoyl”, “substitutedaminosulfonyl”, “substituted amino” or “substituted hydroxyimino” arethe same or different 1 to 3 substituents selected from those groupswhich include (1) alkyl being optionally substituted with hydroxy,alkoxy, amino, mono- or di-alkylamino, carbamoyl, tetrahydrofuryl orpyridyl, (2) cycloalkyl, (3) hydroxy, (4) alkoxy, (5) cyano, (6)halogen, (7) mono- or di-alkylamino, (8) amino being optionallysubstituted with alkanoyl, alkoxyalkanoyl or alkoxycarbonyl, (9)pyridyl, (10) carboxyl, (11) formyl, (12) alkanoyl being optionallysubstituted with mono- or di-alkylamino, hydroxy, alkoxy or alkanoyloxy,(13) cycloalkylcarbonyl, (14) alkoxycarbonyl, (15) oxo, (16)alkylsulfonyl, or the like.

In the compound [I-A], a preferable substituent in substitutedtetrazolyl on R¹ and R² includes alkyl or the like.

A preferable substituent in substituted carbamoyl in R³ and R⁴ includesalkyl or the like, and it may be the same or different 1 to 2 groups.

A preferable substituent in substituted aryl, substituted aryloxy andsubstituted phenyl on R³ and R⁴ includes cyano, halogen atom, alkoxy,alkyl, mono- or di-alkylamino or the like, particularly cyano or halogenatom. The substituent may be the same or different 1 to 3 groupsselected from these groups.

A preferable substituent in substituted heteroaryl, substitutedpyrazolyl, substituted imidazolyl, substituted thiazolyl, substitutedtriazolyl, substituted pyridyl and substituted pyrimidinyl on R³ and R⁴includes alkyl, mono- or di-alkylamino or the like, particularly alkyl.The substituent may be the same or different 1 to 2 groups selected fromthese groups.

A preferable substituent in substituted heterocycle, substitutedpyrrolidinyl and substituted thiacyclohexyl on R³ and R⁴ includes oxo,alkoxycarbonyl, alkyl, alkanoyl or the like, particularly oxo or alkyl.The substituent may be the same or different 1 to 2 groups selected fromthese groups.

A preferable substituent in substituted cycloalkyl and substitutedcyclopentyl in R³ and R⁴ includes oxo, hydroxy or the like, particularlyhydroxy.

A preferable substituent in substituted carbamoyl in R⁵ includes alkoxy,alkyl, cycloalkyl, hydroxyalkyl, dialkylaminoalkyl, cycloalkyl,tetrahydrofurylalkyl, pyridylalkyl, alkoxy, pyridyl or the like,particularly hydroxyalkyl, dialkylaminoalkyl, pyridylalkyl, pyridyl orthe like. The substituent may be the same or different 1 to 2 groupsselected from these groups.

A preferable substituent in substituted aminosulfonyl in R⁵ includesalkyl or the like, and the substituent may be the same or different 1 to2 groups selected from these groups.

A preferable substituent in substituted heterocycle, substitutedheterocyclyl-carbonyl, substituted heterocyclyl-sulfonyl, substitutedpiperazinyl, substituted piperazinylsulfonyl, substitutedhomopiperazinyl, substituted piperidinyl, substituted morpholinyl andsubstituted thiomorpholinyl in R⁵ includes alkoxycarbonylamino, hydroxy,hydroxyalkyl, alkanoylamino, alkoxyalkanoylamino, oxo, alkyl, formyl,alkanoyl, hydroxyalkanoyl, cycloalkylcarbonyl, carboxyl, alkoxycarbonyl,alkoxyalkanoyl, alkanoyloxyalkanoyl, mono- or di-alkylaminoalkanoyl,alkylsulfonyl or the like, particularly oxo, alkyl, formyl, alkanoyl,hydroxyalkanoyl, cycloalkylcarbonyl, alkoxycarbonyl, alkoxyalkanoyl,alkanoyloxyalkanoyl or alkylsulfonyl. The substituent may be the same ordifferent 1 to 3 groups selected from these groups.

A preferable substituent in substituted amino in R⁵ includes alkyl,alkoxyalkyl, pyridyl, pyridylalkyl, dialkylaminoalkyl, carbamoylalkyl orthe like. The substituent may be the same or different 1 to 2 groupsselected from these groups.

A preferable substituent in substituted hydroxyimino in R⁵ includesalkoxycarbonyl or the like.

In the compound [I-A], the aryl in Ring A includes preferably phenyl.

The heteroaryl in Ring A includes preferably thienyl or pyridyl,particularly pyridyl.

The heterocycle in Q includes, for example, 5 to 6-membered monocyclicheterocycle, specifically tetrahydrofuryl, pyrrolidinyl,tetrahydropyranyl, thiacyclohexyl, piperidinyl or the like, particularlytetrahydrofuryl.

The heteroaryl in Ring T includes, for example, 5 to 9-memberedmonocyclic or bicyclic aromatic ring, specifically thiazolyl,thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl, thiazolopyridinyl orthe like. The heterocycle in Ring T includes, for example, 9-memberedbicyclic aromatic ring, specifically cyclohexanothiazolyl,dihydrothiazolopyridinyl or the like.

The aryl in R³ and R⁴ includes preferably phenyl.

The heteroaryl in R³ and R⁴ includes, for example, 5 to 6-memberedmonocyclic aromatic ring, specifically pyrazolyl, imidazolyl,isoxazolyl, thiazolyl, triazolyl, pyridyl, pyrimidinyl or the like.

The heterocycle in R³ and R⁴ includes, for example, 5 to 6-memberedmonocyclic heterocycle, specifically pyrrolidinyl, tetrahydrofuryl,dioxolanyl, piperidinyl, thiacyclohexyl or the like.

The cycloalkyl in R³ and R⁴ includes preferably 3 to 6-memberedcycloalkyl, specifically cyclopropyl or cyclopentyl.

The heterocycle in R⁵ includes, for example, 4 to 6-membered monocyclicheterocycle, specifically azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl or the like.

Among the compound [I-A], a preferable compound includes a compoundwherein Ring A is phenyl, Q is 3-tetrahydrofuryl, Ring T is 2-thiazolyl,one of R¹ and R² is hydrogen atom, the other is cyclopropylsulfonyl,both of R³ and R⁴ are hydrogen atom, R⁵ is piperazinyl substituted alkylbeing optionally substituted with 1 to 3 substituents selected fromalkyl, oxo, alkanoyl and alkoxyalkanoyl.

Other preferable compound among the compounds [I] of the presentinvention includes a compound described in any of all EXAMPLES.

The following terms used herein mean as defined below.

A “halogen atom” includes fluorine atom, chlorine atom, bromine atom oriodine atom, preferably fluorine atom or chlorine atom.

An “alkyl”, which includes “alkyl” moiety in a group bound with othergroups such as “alkylthio” or “hydroxyalkyl” (the same for other groupsdefined hereinafter), includes, for example, straight- or branched-chainalkyl of C₁₋₆, preferably C₁₋₄, specifically methyl, ethyl, propyl,isopropyl, isobutyl, tert-butyl, pentyl, hexyl or the like.

An “alkenyl” includes, for example, straight- or branched-chain alkenylof C₂₋₆, preferably C₂₋₄, specifically vinyl, propenyl, isopropenyl,butenyl, pentenyl, hexenyl or the like.

An “alkynyl” includes, for example, straight- or branched-chain alkynylof C₂₋₆, preferably C₂₋₄, specifically acetylenyl, propynyl, butynyl,pentynyl, hexynyl or the like.

An “alkoxy” includes, for example, straight- or branched-chain alkoxy ofC₁₋₆, preferably C₁₋₄, specifically methoxy, ethoxy, propoxy,isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy or the like.

An “alkanoyl” includes, for example, straight- or branched-chainalkanoyl of C₂₋₇, preferably C₂₋₅, specifically acetyl, propionyl,butyryl, pentanoyl or the like.

A “cycloalkyl” includes, for example, cycloalkyl of C₃₋₈, preferablyC₃₋₆, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl.

An “aryl” includes 6 to 14-membered, preferably 6 to 10-memberedmonocyclic, bicyclic or tricyclic aromatic hydrocarbon, specificallyphenyl, naphthyl, phenanthryl, anthryl or the like, preferably phenyl inparticular.

A “heteroaryl” includes 4 to 10-membered, preferably 5 to 9-membered,monocyclic or bicyclic aromatic hydrocarbon wherein 1 to 3 carbon atomsare substituted with heteroatoms independently selected from oxygenatom, sulfur atom and nitrogen atom, specifically thienyl, thiazolyl,pyrazolyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridyl,pyrimidinyl, pyrazinyl, quinolyl, benzothiazolyl, thiazolopyridinyl,thiazolopyrazinyl, thiazolopyrimidinyl or the like.

A “heterocycle” includes 4 to 10-membered, preferably 4 to 9-membered,monocyclic or bicyclic non-aromatic hydrocarbon wherein 1 to 3 carbonatoms are substituted with heteroatoms independently selected fromoxygen atom, sulfur atom and nitrogen atom, specifically oxetanyl,azetidinyl, pyrrolidinyl, tetrahydrofuryl, dioxolanyl, piperidinyl,piperazinyl, homopiperazinyl, tetrahydropyranyl, thiacyclohexyl,morpholinyl, thiomorpholinyl, cyclohexanothiazolyl,dihydrothiazolopyridinyl, tetrahydrothiazolopyridinyl or the like.

Alternatively, illustrative embodiments of “halogen atom”, “alkyl”,“alkenyl”, “alkynyl”, “alkoxy”, “alkanoyl”, “cycloalkyl”, “aryl”,“heteroaryl”, “heterocycle” include those specifically indicated inEXAMPLES.

Additionally, each term is explained depending on each symbol (A, Q, T,R¹-R⁶) of the compound [I].

A preferable “aryl” in Ring A includes phenyl.

A preferable “heteroaryl” in Ring A includes thienyl, pyridyl,particularly pyridyl.

A preferable “cycloalkyl” in Q includes, for example, 5 to 6-memberedmonocyclic cycloalkyl, specifically cyclopentyl, cyclohexyl or the like,particularly cyclopentyl.

A preferable “heterocycle” in Q includes, for example, 4 to 6-memberedmonocyclic heterocycle optionally having 1 to 3 heteroatomsindependently selected from oxygen atom, sulfur atom and nitrogen atom,specifically oxetanyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl or the like, particularlytetrahydrofuryl.

A “heteroaryl” in Ring T includes, for example, 5 to 9-memberedmonocyclic, bicyclic heteroaryl optionally having 1 to 3 heteroatomsindependently selected from oxygen atom, sulfur atom and nitrogen atom,specifically thiazolyl, pyrazolyl, thiadiazolyl, pyridyl, pyrazinyl,benzothiazolyl, thiazolopyridinyl, thiazolopyrazinyl,thiazolopyrimidinyl, quinolyl or the like. A preferable one among themis thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, benzothiazolyl,thiazolopyridinyl, thiazolopyrazinyl, thiazolopyrimidinyl, morepreferably thiazolyl, thiadiazolyl, pyrazinyl, thiazolopyridinyl,thiazolopyrazinyl, particularly thiazolyl, thiazolopyridinyl, furtherparticularly thiazolyl.

A “heterocycle” in Ring T includes, for example, 5 to 9-memberedmonocyclic, bicyclic heterocycle optionally having 1 to 3 heteroatomsindependently selected from oxygen atom, sulfur atom and nitrogen atom,preferably 9-membered bicyclic heterocycle, specificallycyclohexanothiazolyl, dihydrothiazolopyridinyl or the like.

A “cycloalkyl” of cycloalkylsulfonyl in R² includes, for example, 3 to4-membered cycloalkyl, specifically cyclopropyl, cyclobutyl or the like,preferably cyclopropyl in particular.

A “heterocycle” which is the substituent of the substituted orunsubstituted alkyl which is the substituent of substituted orunsubstituted aminosulfonyl in R² includes, for example, 5 to 9-memberedmonocyclic, bicyclic heterocycle optionally having 1 to 3 heteroatomsindependently selected from oxygen atom, sulfur atom and nitrogen atom,preferably 5-membered monocyclic heterocycle. Particularly,tetrahydrofuryl is preferable.

A “heterocycle” of substituted or unsubstituted heterocyclyl-sulfonyl inR² includes, for example, 5 to 9-membered monocyclic, bicyclicheterocycle optionally having 1 to 3 heteroatoms independently selectedfrom oxygen atom, sulfur atom and nitrogen atom, preferably 5 to7-membered monocyclic heterocycle, specifically azetidinyl,pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, oxazepidinyl, perhydrodiazepinyl.

A “heteroaryl” of substituted or unsubstituted heteroaryl in R³ and R⁴includes, for example, 5 to 9-membered monocyclic, bicyclic heteroaryloptionally having 1 to 3 heteroatoms independently selected from oxygenatom, sulfur atom and nitrogen atom, preferably 5 to 6-memberedmonocyclic heteroaryl optionally having 1 to 3 nitrogen atoms,specifically pyrazolyl, imidazolyl, thiazolyl, triazolyl, pyridyl,pyrimidinyl or the like, particularly pyrimidinyl.

A “cycloalkyl” of substituted or unsubstituted cycloalkyl in R³ and R⁴includes preferably 3 to 6-membered monocyclic cycloalkyl, specificallycyclopropyl, cyclopentyl.

A “heterocycle” of substituted or unsubstituted heterocycle which is thesubstituent of substituted or unsubstituted alkyl in R⁵ includes, forexample, 5 to 9-membered monocyclic, bicyclic heterocycle optionallyhaving 1 to 3 heteroatoms independently selected from oxygen atom,sulfur atom and nitrogen atom, preferably 4 to 6-membered monocyclicheterocycle optionally having 1 to 3 nitrogen atoms, specificallyazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, perhydrodiazepinyl, octahydropyrrolo[1,2-a]piperazinylor the like. More preferable one among them is piperazinyl, morpholinyl,particularly piperazinyl.

A “heterocycle” of the substituted or unsubstituted heterocyclyl-oxywhich is the substituent of substituted alkyl in R⁵ includes, forexample, 5 to 9-membered monocyclic, bicyclic heterocycle optionallyhaving 1 to 3 heteroatoms independently selected from oxygen atom,sulfur atom and nitrogen atom, preferably 4 to 6-membered monocyclicheterocycle optionally having 1 to 3 nitrogen atoms, specificallyazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, perhydrodiazepinyl, octahydropyrrolo[1,2-a]piperazinylor the like. More preferable one among them is piperidinyl.

The compound [I] of the present invention includes a mixture ofstereoisomers, or each stereoisomer with pure or substantively pureforms. For example, the compound [I] can exist in enantiomer ordiastereomer or a mixture thereof when the compound of the presentinvention has one or more asymmetric centers in any of carbon atoms. Thecompound of the present invention includes its isomers or a mixturethereof. Also, in case that the compound [I] of the present inventioncontains double bonds, geometric isomers (cis isomer, trans isomer) mayexist and in case that the compound [I] of the present inventioncontains unsaturated bonds such as carbonyl, tautomers may exist, butthe compound of the present invention includes all these isomers or amixture thereof.

A pharmaceutically acceptable salt of the compound [I] includes, forexample, an inorganic acid salt such as hydrochloride, sulfate,phosphate or hydrobromide, or an organic acid salt such as acetate,fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylateor maleate. Also, in case of having a substituent such as carboxyl, saidsalt includes a salt with a base such as, for example, alkali metal saltsuch as sodium salt or potassium salt, or alkali earth metal salt suchas calcium salt.

The pharmaceutically acceptable salt of the compound [I] of the presentinvention includes also an intramolecular salt, and the compounds [I]and their salts may be in the form of a solvate thereof such as ahydrate.

The compound [I] of the present invention or a pharmaceuticallyacceptable salt thereof can be formulated to a pharmaceuticalcomposition comprising a therapeutically effective amount of thecompound and a pharmaceutically acceptable carrier. The pharmaceuticallyacceptable carrier can include diluents, binding agents (syrup, gumacacia, gelatin, sorbit, tragacanth or polyvinylpyrrolidone), excipients(lactose, sucrose, cornstarch, potassium phosphate, sorbit or glycine),lubricants (magnesium stearate, talc, polyethylene glycol or silica),disintegrants (Irish potato starch) and wetting agents (sodium laurylsulfate), or the like.

The compound [I] of the present invention or a pharmaceuticallyacceptable salt thereof can be administered orally or parenterally andused in an appropriate pharmaceutical formulation. The appropriatepharmaceutical formulation for oral administration includes, forexample, solid formulations such as tablet, granule, capsule or powder,or in the form of a solution, a suspension or an emulsion. Theappropriate pharmaceutical formulation for parenteral administrationincludes a suppository, an injectable solution or an intravenous fluidpreparation using distilled water for injection, saline or glucoseaqueous solution, or an inhaler, or the like.

The compound [I] of the present invention or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical formulation thereof can becombined with other one or more medicines selected from antidiabetic andantihyperglycemic agents. In this case, the concept of the term“combine” includes administering with these other medicinessimultaneously or separately with optional interval as well asadministering as one pharmaceutical formulation formulated together withthese other medicines. These other medicines include sulfonylurea (forexample, glyburide, glimepiride, glipiride, glipizide, chlorpropamide,gliclazide, glisoxepide, acetohexamide, glibonuride, tolbutamide,tolazamide, carbutamide, gliquidone, glihexamid, phenbutamide,tolcyclamide or the like), biguanide (for example, metformin,phenformin, buformin or the like), glucagon antagonist (for example,peptidic or nonpeptidic glucagon antagonist), glucosidase inhibitor (forexample, acarbose, miglitol or the like), insulin sensitizer (forexample, troglitazone, rosiglitazone, pioglitazone or the like),antiobesity agent (for example, sibutramine, orlistat or the like) orthe like.

The dose of the compound [I] of the present invention or apharmaceutically acceptable salt thereof depends on methods ofadministration, ages, body weights or conditions of patients, butusually about 0.01 to about 100 mg/kg per day, preferably about 0.1 toabout 10 mg/kg.

The compound [I] of the present invention can be prepared according tothe following methods.

(In the above scheme, Z¹ is halogen atom, hydroxy or alkoxy, Z² ishydrogen atom or alkyl, Z³ is hydroxy, halogen atom or arylsulfonyloxy,alkylsulfonyloxy, Z⁴ is halogen atom, dialkoxyboryl, dihydroxyboryl ortrialkylstannyl, lithio, Z⁵ is hydrogen atom, halogen atom,dialkoxyboryl, dihydroxyboryl or trialkylstannyl, lithio, and the othersymbols have the same meanings as mentioned above.)

-   (1) The reaction of preparing the compound [VI] (Z² is alkyl) from    the compound [VII] (Z⁵ is hydrogen atom) and the compound [VIII] (Z¹    is halogen atom, Z² is alkyl) can be carried out under so-called    Friedel-Crafts reaction condition. For example, the reaction can be    carried out in an appropriate solvent (chloroform, methylene    chloride, nitromethane or the like) in the presence of an    appropriate acid (aluminum chloride or the like).

The compound [VI] (Z² is alkyl) can be also prepared by reacting thecompound [VII] (Z⁵ is dialkoxyboryl, dihydroxyboryl or trialkylstannyl)with the compound [VIII] (Z¹ is halogen atom, Z² is alkyl) in anappropriate solvent (THF, methylene chloride, dioxane, water, DMF,toluene, 1,2-dimethoxyethane or the like, or a mixture thereof) using ametal catalyst (for example, dichlorobis(triphenylphosphine)palladium,tetrakis-(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium,dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium or the like),and the process preferably proceeds at −78° C. to 200° C.

Additionally, the compound [VI] (Z² is alkyl) can be also prepared byreacting the compound [VII] (Z⁵ is lithio) with the compound [VIII] (Z¹is alkoxy, Z² is alkyl) in an appropriate solvent (THF, dioxane, DMF,toluene, 1,2-dimethoxyethane or the like, or a mixture thereof), and theprocess can be preferably carried out at −78° C. to 200° C. Also, incase of using the compound [VII] (Z⁵ is halogen atom), the compound [VI](Z² is alkyl) can be prepared by converting the compound [VII] (Z⁵ ishalogen atom) into the compound [VII] (Z⁵ is lithio) with an appropriatealkyllithium (n-butyllithium, sec-butyllithium, t-butyllithium or thelike) in an appropriate solvent (THF, diethyl ether, toluene,1,2-dimethoxyethane or the like, or a mixture thereof) to convert,followed by reacting with the compound [VIII] (Z¹ is alkoxy, Z² isalkyl) in the similar manner as the above-mentioned.

-   (2) The reaction of the compound [VI] (Z² is alkyl) with    hydroxylamine or a salt thereof with an appropriate acid    (hydrochloride, sulfate or the like) can be carried out in any    conventional manner converting ketone into hydroxyimino. For    example, the reaction can be carried out in an appropriate solvent    (alcoholic solvent such as methanol, ethanol, or THF, dioxane, water    or the like, or a mixed solvent thereof) in the presence or absence    of a base. The base used in the reaction includes pyridine,    picoline, lutidine, N,N-dimethylaniline, triethylamine or the like.    An oxime generated in a cis-isomer or a mixture of cis- and    trans-isomers can be converted into the desired trans-isomer by    treating with acid (trifluoroacetic acid, acetic acid, hydrochloric    acid, sulfuric acid, phosphoric acid or the like). Also an oxime    generated in the reactions described below can also be converted    into the desired trans-isomer by treating in the similar manner as    the above.-   (3) The reaction of the compound [IV] (Z² is alkyl) with the    compound [V] wherein Z³ is hydroxy can be carried out by using, in    the presence of triphenylphosphine, an activating agent (diethyl    azodicarboxylate, diisopropyl azodicarboxylate or the like), or, in    absence of triphenylphosphine, cyanomethyl tri-n-butyl phosphorane    or the like in an appropriate solvent (THF, methylene chloride or    the like) (so-called Mitsunobu reaction). Also, the reaction with    the compound [V] wherein Z³ is halogen atom, arylsulfonyloxy or    alkylsulfonyloxy can be carried out in an appropriate solvent    (acetone, ethanol, THF, dimethyl sulfoxide, DMF, dioxane,    N,N-dimethylacetamide, N-methylpyrrolidone or the like, or a mixed    solvent thereof) in the presence of a base such as potassium    carbonate, potassium tert-butoxide, sodium hydride, cesium carbonate    or the like. A product resulted in this way can be converted into    the compound [II] (Z² is hydrogen atom) in any conventional manner    hydrolyzing alkoxycarbonyl to carboxyl, for example, by treating    with lithium hydroxide, sodium hydroxide, potassium carbonate or the    like in an appropriate solvent (alcoholic solvent such as methanol,    ethanol, or THF, dioxane, water or the like, or a mixed solvent    thereof) to hydrolyze Z² group.-   (4) The reaction of the compound [II] (Z² is hydrogen atom) with the    compound [III] can be carried out in an appropriate solvent in the    presence or absence of a condensing agent by using any conventional    method for amide formation usually used in peptide synthesis or the    like. As the condensing agent, any of    N-ethyl-N′-(3-diethylaminopropyl)-carbodiimide,    N,N′-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide,    N,N′-carbonyldiimidazole, diphenyl phosphoryl azide,    benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluoro-phosphate,    4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,    fluoro-N,N,N′,N′-tetramethylformamidinium hexafluoro-phosphate or    the like can be preferably used. As the solvent, any of a single    solvent or a mixed solvent of water, methanol, isopropanol, ethanol,    methylene chloride, THF, dioxane, DMF, dimethylacetamide, chloroform    or the like can be preferably used. The reaction preferably proceeds    at −78° C. to 100° C., more preferably at −25° C. to 25° C. The    proceed of the reaction can be accelerated by adding an inorganic    base such as potassium carbonate, sodium carbonate, sodium    bicarbonate or an organic base such as triethylamine,    diisopropylethylamine, N-methylmorpholine, pyridine,    N,N-dimethylaminopyridine, picoline, lutidine or the like as a base,    and N-hydroxysuccinimide,    3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole,    N,N-dimethylaminopyridine or N-hydroxybenzotriazole or the like as    an additive.

The reaction from the compound [II] (Z² is hydrogen atom) to thecompound [I] can be carried out by converting the compound [II] (Z² ishydrogen atom) into a reactive intermediate such as acid chloride or amixed acid anhydride, followed by reacting with the compound [III]. Theconversion into acid chloride can be preferably carried out by usingthionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphoruspentachloride, or triphenylphosphine in the presence of carbontetrachloride, or the like, and the conversion into a mixed acidanhydride can be carried out by using diphenyl phosphoryl chloride,diethyl phosphorocyanidate, methanesulfonyl chloride, ethylchloroformate, isobutyl chloroformate or the like in the presence of abase such as triethylamine. As the solvent, any of a single solvent or amixed solvent of methylene chloride, chloroform, THF, DMF or the likecan be preferably used. The reaction preferably proceeds at −78° C. to100° C., more preferably −25° C. to 25° C. The reaction of an acidchloride or a mixed acid anhydride resulted in this way with thecompound [III] proceeds in the presence of a base such as pyridine,triethylamine, N,N-dimethylaminopyridine, diisopropylethylamine or thelike preferably at −78° C. to 100° C., more preferably −25° C. to 25° C.and as the solvent, any of a single solvent or a mixed solvent ofmethylene chloride, chloroform, THF, DMF or the like can be preferablyused.

-   (5) The reaction of the compound [VI] (Z² is hydrogen atom or alkyl)    with the compound [III] can be carried out in case that Z² is    hydrogen atom in the similar manner as the reaction of the above    (4), or in case that Z² is alkyl via the compound [VI′] and the    compound [X′] below. The conversion from the compound [VI]    (Z²=alkyl) to the compound [VI′] (Z² is hydrogen atom) can be    carried out in any conventional manner reducing ketone to alcohol,    for example, by treating with a reducing agent such as zinc    borohydride, sodium triacetoxyborohydride, sodium borohydride or the    like in an appropriate solvent (water, methanol, ethanol,    chloroform, methylene chloride or the like, or a mixed solvent    thereof), followed by hydrolysis in any conventional manner    hydrolyzing alkoxycarbonyl to carboxyl, for example, by treating    with lithium hydroxide, sodium hydroxide or the like in an    appropriate solvent (methanol, ethanol, THF, dioxane, water or the    like, or a mixed solvent thereof) to hydrolyze Z² group.

The reaction of the compound [VI′] (Z² is hydrogen atom) with thecompound [III] can be carried out in the similar manner as the reactionof the above (4).

The conversion from the compound [X′] to the compound [X] can be carriedout in any conventional manner oxidizing alcohol to ketone, for example,by dimethylsulfoxide oxidation using an activating agent such as oxalylchloride (Swern oxidation), or by using an oxidizing agent (activatedmanganese dioxide, sulfur trioxide-pyridine complex,1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, pyridiniumchlorochromate, pyridinium dichromate or the like) in the presence orabsence of a base (triethylamine or the like) in an appropriate solvent(dimethylsulfoxide, chloroform, methylene chloride or the like).

-   (6) The reaction from the compound [X] to the compound [IX] can be    carried out in the similar manner as the reaction of the above (2).-   (7) The reaction from the compound [IX] and the compound [V] to the    compound [I] can be carried out in the similar manner as the    reaction of the above (3).-   (8) The reaction of the compound [VI] with the compound [XI] can be    carried out in the similar manner as the reaction of the above (2)    by using O-substituted hydroxylamine or a salt thereof    (alkyloxyamine, cycloalkyloxyamine, heterocyclyl-oxyamine,    benzyloxyamine or the like) as an alternative to hydroxylamine in    the reaction of (2).-   (9) The reaction of the compound [X] with the compound [XI] can be    carried out in the similar manner as the reaction of the above (8).-   (10) The reaction of the compound [XI] with the compound [VIII] (Z¹    is halogen atom or hydroxy, Z² is alkyl) can be carried out in any    conventional manner of amide formation usually used in peptide    synthesis or the like, for example in the similar manner as the    reaction of the above (4).-   (11) The reaction from the compound [XIII] (Z² is alkyl) to the    compound [XII] (Z⁴ is hydrogen atom) can be carried out by using any    conventional method for converting amide into haloimino, preferably    the manner of reference: WO9520569, for example, by using the    compound [XIII] (Z² is alkyl) with a halogenating agent (phosphorus    oxychloride, phosphorus pentachloride or the like) in an appropriate    solvent (acetonitrile, chloroform, methylene chloride, THF or the    like, or a mixed solvent thereof). The reaction can be also carried    out by using carbon tetrachloride, carbon tetrabromide,    N-bromosuccinimide, N-chlorosuccinimide, iodine or the like in the    presence of triphenylphosphine.-   (12) The reaction from the compound [XII] (Z² is alkyl) and the    compound [VII], for example in case that Z⁵ is dihydroxyboryl, to    the compound [II] (Z² is alkyl) can be carried out by using a metal    catalyst (for example, dichlorobis(triphenylphosphine)palladium,    tetrakis(triphenylphosphine)palladium,    tris(dibenzylideneacetone)-dipalladium,    dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium or the like)    in an appropriate solvent (for example, dioxane, toluene, THF,    1,2-dimethoxyethane, methanol, ethanol, DMF, N-methylpyrrolidone or    the like, or a mixed solvent thereof) in the presence of a base    (sodium carbonate, potassium carbonate, triethylamine,    diisopropylethylamine or the like). The reaction preferably proceeds    under inert gas such as argon at room temperature to 200° C. or in    the exposure of microwave.

The compound [I] can be converted further in the following methods.

-   (A) The compound containing sulfinyl (SO) or sulfonyl (SO₂) on R¹-R⁶    among the objective compound [I] of the present invention can be    prepared by oxidation using any conventional method for converting    the corresponding sulfide compound into a sulfinyl or sulfonyl    compound. For example, the oxidation can be carried out by treating    with an oxidizing agent in an appropriate solvent (methylene    chloride, chloroform, THF, methanol, water, or the like or a mixed    solvent thereof. As the oxidizing agent, peracids such as hydrogen    peroxide, m-chloroperbenzoic acid, peracetic acid or the like as    well as Oxone™ (“a mixture of potassium peroxybisulfate, dipotassium    sulfate and potassium bisulfate” manufactured by DuPont) can be    preferably used, and the reaction can be preferably carried out at    −78° C. to 100° C.-   (B) The compound having a group of the formula:    —CH₂N(R¹¹)(R¹²),    wherein R¹¹ and R¹² are substituents of the substituted amino group    described herein or R¹¹ and R¹² form together with N atom of said    amino group a heterocycle having 1 to 3 heteroatoms independently    selected from oxygen atom, sulfur atom and nitrogen atom wherein the    heterocycle may be substituted,    on R¹-R⁶ among the objective compound [I] can be also prepared by    so-called “reductive amination”, by reacting the compound wherein    the corresponding site is formyl with a substituted or unsubstituted    amine of the formula:    HN(R¹¹)(R¹²),    wherein the symbols have the same meanings as mentioned above    (hereinafter, this compound is referred to as “a substituted or    unsubstituted amine”, and the group after removing of hydrogen atom    from the substituted or unsubstituted amine is referred to as “a    substituted or unsubstituted amino”),    under reductive condition. The reaction can be carried out in any    conventional manner of reductive amination. For example, the    reaction can be preferably carried out by using a reducing agent    (sodium borohydride, sodium triacetoxyborohydride, sodium    cyanoborohydride or the like) in an appropriate solvent (methanol,    methylene chloride, chloroform or the like) at −78° C. to 100° C.-   (C) Among the objective compound [I], the compound wherein nitrogen    atom on R¹-R⁶ is substituted with a substituted or unsubstituted    alkanoyl such as alkanoyl, cycloalkylcarbonyl, alkoxyalkanoyl,    alkanoyloxyalkanoyl or the like, which is simply referred to as    substituted or unsubstituted alkanoyl hereinafter, can be also    prepared by alkanoylation of the compound wherein the corresponding    N atom is unsubstituted (for example, the compound wherein R⁵ is    piperazinylmethyl, piperazinylcarbonyl or piperazinyl-sulfonyl or    the like). The alkanoylation can be carried out by using any    conventional method of amide formation usually used in peptide    synthesis or the like. For example, the alkanoylation can be    preferably carried out by using acid chloride, acid anhydride or    ester in an appropriate solvent (methylene chloride, THF, DMF,    N,N-dimethylacetamide, chloroform or a mixed solvent thereof) in the    presence or absence of a base (triethylamine, pyridine or the like)    at −78° C. to 100° C. The reaction can be also carried out, for    example, in an appropriate solvent in the presence or absence of a    condensing agent. As the condensing agent, any of    N-ethyl-N′-(3-diethylaminopropyl)-carbodiimide,    N,N′-dicyclohexylcarbodiimide, 1-methyl-2-bromo-pyridinium iodide,    N,N′-carbonyldiimidazole, diphenylphosphoryl azide,    benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluoro-phosphate,    4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride,    fluoro-N,N,N′,N′-tetramethylformamidinium hexafluoro-phosphate or    the like can be preferably used. As the solvent, any of a single    solvent or a mixed solvent of water, methanol, isopropanol, ethanol,    methylene chloride, THF, DMF, N,N-dimethylacetamide, chloroform or    the like can be preferably used. The reaction preferably proceeds at    −78° C. to 100° C., more preferably −25° C. to 25° C. The proceed of    the reaction can be promoted by adding potassium carbonate, sodium    carbonate, sodium bicarbonate or triethylamine,    diisopropylethylamine, N-methylmorpholine, pyridine,    N,N-dimethylaminopyridine, picoline, lutidine or the like as a base,    and N-hydroxysuccinimide or    3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole,    N,N-dimethylaminopyridine, N-hydroxybenzotriazole or the like as an    additive.-   (D) The compound having substituted or unsubstituted amino-carbonyl,    i.e. substituted or unsubstituted carbamoyl, on R¹-R⁶ among the    objective compound [I] can be prepared by reacting the compound    wherein the corresponding site is carboxy with a substituted or    unsubstituted amine. The reaction can be carried out in the similar    manner as the reaction of the above (C).-   (E) The compound wherein R⁵ or R⁶ has substituted or unsubstituted    alkoxymethyl, or substituted or unsubstituted heteroarylmethyl among    the objective compound [I] can be also prepared by converting the    compound wherein the corresponding site is hydroxymethyl into    alkanoylmethyl, preferably acetyloxymethyl, in any conventional    esterification manner, followed by condensing substituted or    unsubstituted alkanol, cycloalkanol, alkylthio or a heterocycle    compound having hydroxyl group, or substituted or unsubstituted    heteroaryl compound having hydrogen atom on nitrogen atom, for    example pyrazole or the like. The condensing reaction can be    preferably carried out as neat or in an appropriate solvent (THF,    dioxane, methylene chloride, chloroform, toluene, benzene or the    like) in the presence or absence of an acid (p-toluenesulfonic acid,    hydrochloric acid, sulfuric acid, trifluoroacetic acid or the like)    at −78° C. to 200° C., more preferably 25° C. to 100° C.-   (F) The compound having hydroxymethyl on R¹-R⁶ among the objective    compound [I] can be prepared by reducing the compound wherein the    corresponding site is formyl in any conventional manner by reducing    formyl to alcohol. For example, the reaction can be preferably    carried out by using a reducing agent (sodium borohydride, sodium    triacetoxyborohydride, diborane, diisobutylaluminum hydride, lithium    aluminum hydride or the like) in an appropriate solvent (methanol,    ethanol, methylene chloride, chloroform, dioxane, THF or the like)    at −78° C. to 100° C.-   (G) The compound having carboxyl on R¹-R⁶ among the objective    compound [I] can be prepared by oxidizing the compound wherein the    corresponding site is formyl in any conventional manner by oxidizing    formyl to carboxyl. The oxidation can be preferably carried out by,    for example, using an oxidizing agent (sodium chlorite, potassium    permanganate, pyridinium dichromate or the like) in an appropriate    solvent (DMF, dimethylsulfoxide, acetone, tert-butanol, water,    methylene chloride, chloroform or the like) at −78° C. to 100° C.-   (H) The compound having alkoxycarbonyl on R¹-R⁶ among the objective    compound [I] can be also prepared by esterifying the compound    wherein the corresponding site is carboxyl in any conventional    manner by esterifying carboxyl to alkoxycarbonyl. The esterification    can be preferably carried out by, for example, using an acid    (sulfuric acid, hydrochloric acid, p-toluenesulfonic acid) in an    appropriate solvent (methanol, ethanol, isopropanol, tert-butanol or    the like) at −78° C. to 200° C., more preferably 0° C. to 100° C.

Additionally, the esterification can be also carried out by converting acarboxyl compound to a reactive intermediate such as an acid halide witha halogenating agent (oxalyl chloride, thionyl chloride or the like) inan appropriate solvent (methylene chloride, chloroform, THF, dioxane orthe like), followed by using alkanol (methanol, ethanol, isopropanol orthe like) at −78° C. to 200° C.

-   (I) The compound having carboxyl on R¹-R⁶ among the objective    compound [I] can be also prepared by hydrolyzing the compound    wherein the corresponding site is alkoxycarbonyl in any conventional    manner of ester hydrolysis. The hydrolysis can be preferably carried    out by using a base (sodium hydroxide, potassium hydroxide,    potassium carbonate, lithium hydroxide or the like) in an    appropriate solvent (alcoholic solvent such as methanol, ethanol, or    dioxane, THF, water or the like, or a mixed solvent thereof at    −78° C. to 200° C., more preferably 0° C. to 100° C.

Additionally, the hydrolysis can be also preferably carried out by usingan acid (sulfuric acid, hydrochloric acid or the like) in an appropriatesolvent (THF, dioxane, acetic acid, water or the like, or a mixedsolvent thereof at −78° C. to 200° C.

-   (J) The compound having formyl on R¹-R⁶ among the objective compound    [I] can be also prepared from the compound wherein the corresponding    site is carboxyl in any conventional manner by reducing carboxyl to    aldehyde. The reaction can be preferably carried out by using a    halogenating agent (oxalyl chloride, thionyl chloride or the like)    in an appropriate solvent (methylene chloride, chloroform, THF or    the like, or a mixed solvent thereof) to synthesize acid halide,    followed by reducing the acid halide with a metal catalyst    (palladium carbon, platinum dioxide or the like) under hydrogen at    −78° C. to 200° C.-   (K) The compound having hydroxymethyl on R¹-R⁶ among the objective    compound [I] can be prepared by using any conventional method of    reduction of ester or carboxylic acid to alcohol. For example, the    reaction can be preferably carried out by treating the corresponding    carboxyl or alkoxycarbonyl with a reducing agent (sodium    borohydride, diborane, lithium aluminum hydride, diisobutylaluminum    hydride or the like) in an appropriate solvent (methylene chloride,    chloroform, THF or the like) at −78° C. to 200° C.-   (L) The compound having carboxyl on R¹-R⁶ among the objective    compound [I] can be prepared by using the conventional method of    oxidation of primary alcohol to carboxylic acid. For example, the    reaction can be preferably carried out by using the compound wherein    the corresponding site is hydroxymethyl with an oxidizing agent    (chromium trioxide, pyridinium dichromate or the like) in an    appropriate solvent (methylene chloride, acetone, chloroform, DMF or    the like) at, for example, 0° C. to 100° C.-   (M) The compound having amino on R¹-R⁶ among the objective compound    [I] can be carried out by using any conventional method of reduction    of nitro to amine. For example, the reaction can be carried out by    treating the compound wherein the corresponding site is nitro with a    metal catalyst (palladium carbon, platinum dioxide or the like) in    an appropriate solvent (methanol, ethanol, DMF, THF, dioxane or the    like) under hydrogen at −78° C. to 200° C.

Additionally, the process can be also preferably carried out by using areducing agent (stannous chloride, iron, zinc or the like) in anappropriate solvent (alcoholic solvent such as methanol, ethanol, ormethylene chloride, chloroform, THF, dioxane, acetic acid, water or thelike, or a mixed solvent thereof at −78° C. to 200° C., more preferably0° C. to 100° C.

-   (N) The compound having halogenosulfonyl on R¹-R⁶ among the    objective compound [I] can be prepared by reacting the compound    wherein the corresponding site is amino under so-called Sandmayer    reaction condition to halogenosulfonylate via a diazonium salt. The    formation of a diazonium salt can be preferably carried out by, for    example, using an oxidizing agent (sodium nitrite, isoamyl nitrite,    tert-butyl nitrite or the like) in an appropriate solvent (water,    methylene chloride, chloroform, THF or the like, or a mixed solvent    thereof) in the presence or absence of an appropriate acid    (hydrochloric acid, sulfuric acid or the like) and/or an additive    (cupric chloride or the like) at −78° C. to 200° C. The following    halogenosulfonylation can be carried out by adding a sulfonylating    agent (sulfur dioxide, sodium bisulfite or the like) to the    resulting reaction solution at −78° C. to 200° C.-   (O) The compound having substituted or unsubstituted aminosulfonyl    on R¹-R⁶ among the objective compound [I] can be also prepared by    reacting the compound wherein the corresponding site is    halogenosulfonyl with a substituted or unsubstituted amine. The    reaction can be preferably carried out in an appropriate solvent    (methylene chloride, chloroform, THF, dioxane, water or the like) in    the presence or absence of a base (pyridine, triethylamine, sodium    hydroxide, sodium carbonate or the like) at −78° C. to 200° C.-   (P) The compound having alkylthio, cycloalkylthio, heterocyclyl-thio    on R¹-R⁶ among the objective compound [I] can be also prepared by,    for example, converting the compound wherein the corresponding site    is methylsulfinyl into thiol in the same manner as described in a    literature (Young R. N., et al., Tetrahedron Lett., 1984, 25(17),    1753), followed by reacting with an alkylating agent (haloalkyl,    halocycloalkyl, haloheterocycle compound, alkyl mesylate, cycloalkyl    mesylate, heterocyclyl mesylate, alkyl tosylate, cycloalkyl    tosylate, heterocyclyl tosylate or the like) in the presence or    absence of a base (sodium hydride, cesium carbonate, potassium    carbonate, potassium tert-butoxide, triethylamine,    diazabicycloundecene or the like).-   (Q) The compound having substituted or unsubstituted alkanoyl-amino    on R¹-R⁶ among the objective compound [I] can be also prepared by    alkanoylating the compound wherein the corresponding site is amino.    The alkanoylation can be carried out in a similar manner as in the    reaction of the above (C). Also, the alkanoylation can be carried    out in the compound wherein the corresponding site is secondary    amine as well as primary amine.-   (R) The compound having substituted sulfonylamino such as    alkylsulfonylamino, heteroarylsulfonylamino,    heterocyclyl-sulfonylamino or the like on R¹-R⁶ among the objective    compound [I] can be also prepared by sulfonylating the compound    wherein the corresponding site is amino. The sulfonylation can be    carried out in an appropriate solvent (water, THF, methylene    chloride, chloroform or the like) in the presence or absence of a    base (triethylamine, diisopropylethylamine, pyridine or the like) at    −78° C. to 200° C. Also, the sulfonylation can be carried out in the    compound wherein the corresponding site is secondary amine as well    as primary amine.-   (S) The compound having secondary alcohol on R¹-R⁶ among the    objective compound [I] can be prepared by using any conventional    method for converting ketone into secondary alcohol. For example,    the reaction can be carried out by using the compound having the    corresponding oxo in the similar manner as the reaction of the above    (K).-   (T) The compound having oxo on R¹-R⁶ among the objective compound    [I] can be prepared by using any conventional method for converting    secondary alcohol into ketone. For example, the reaction can be    carried out by dimethylsulfoxide oxidation with an activating agent    such as oxalyl chloride in an appropriate solvent    (dimethylsulfoxide, chloroform, methylene chloride or the like)    (Swern oxidation), or by using an oxidizing agent (activated    manganese dioxide, sulfur trioxide-pyridine complex,    1-hydroxy-1,2-benziodoxol-3(1H)-one-1-oxide,    1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, pyridinium    chlorochromate, pyridinium dichromate or the like) in the presence    or absence of a base (triethylamine or the like).-   (U) The compound having secondary alcohol on R¹-R⁶ among the    objective compound [I] can be prepared by using any conventional    method for converting the compound having formyl into secondary    alcohol. For example, the reaction can be preferably carried out by    using the corresponding formyl and a metal reagent (alkylmagnesium    halide, alkyllithium, dialkylzinc or the like) in an appropriate    solvent (THF, toluene, diethyl ether or the like) at −78° C. to 100°    C.-   (V) The compound having hydroxyamidino on R¹-R⁶ among the objective    compound [I] can be prepared by using any conventional method for    converting cyano group into hydroxyamidino group. For example, the    reaction can be preferably carried out by reacting the compound    having the corresponding cyano with hydroxylamine (or a salt with an    appropriate acid thereof) in the presence or absence of a base    (sodium carbonate, potassium carbonate, sodium hydroxide, potassium    hydroxide, potassium tert-butoxide, triethylamine, pyridine or the    like) in an appropriate solvent (water, methanol, ethanol or the    like, or a mixed solvent thereof) at 0° C. to 100° C.-   (W) The compound having unsubstituted carbamoyl on R¹-R⁶ among the    objective compound [I] can be prepared by using any conventional    method for converting cyano group into unsubstituted carbamoyl    group. For example, the reaction can be preferably carried out by    treating the compound having the corresponding cyano with a base    (sodium hydroxide, potassium hydroxide, potassium tert-butoxide or    the like) in an appropriate solvent (water, methanol, ethanol,    isopropanol or the like, or a mixed solvent thereof) at −20° C. to    100° C.-   (X) The compound having tertiary alcohol on R¹-R⁶ among the    objective compound [I] can be prepared by, for example, reacting the    compound having the corresponding oxo under a condition of the above    (U).-   (Y) The preparation of the compound having optically-active    secondary alcohol on R¹-R⁶ among the objective compound [I] can be    carried out by using any conventional method for resolution of    secondary alcohol compound in enzymatic transesterification. For    example, the preparation can be preferably carried out by treating    the corresponding racemic secondary alcohol with acyl donor (vinyl    acetate or the like) in the presence of enzyme (lipase PS or the    like) in an appropriate solvent (tert-butylmethyl ether, hexane,    diisopropyl ether, THF, diethyl ether, water or the like) at −78° C.    to 100° C.-   (Z) The preparation of the compound having alkyl on R¹-R⁶ among the    objective compound [I] can be carried out by using so-called    catalytic hydrogenation. For example, the compound can be preferably    prepared by treating the compound having the corresponding alkenyl    with a metal catalyst (palladium carbon, platinum dioxide or the    like) under hydrogen in an appropriate solvent (methanol, ethanol,    DMF, THF, acetic acid or the like, or a mixed solvent thereof) at    0° C. to 200° C.-   (AA) The preparation of the compound having 1,2-diol on R¹-R⁶ among    the objective compound [I] can be preferably carried out by, for    example, treating the compound having the corresponding alkenyl with    an oxidizing agent (osmium tetroxide, ruthenium tetroxide, sodium    periodate or the like) in an appropriate solvent (water, acetone,    THF, acetonitrile, ethyl acetate or the like, or a mixed solvent    thereof) at 0° C. to 100° C.-   (BB) The preparation of the compound having halogen atom on R¹-R⁶    among the objective compound [I] can be carried out by using any    conventional method for halogenation of alcohol. For example, the    preparation can be preferably carried out by treating the    corresponding alcohol with carbon tetrabromide in the presence of    triphenylphosphine in an appropriate solvent (methylene chloride,    chloroform or the like) at 0° C. to 100° C.-   (CC) The preparation of the compound having unsubstituted and    substituted alkylthio, heteroarylthio or arylthio on R¹, R², R⁵ or    R⁶ among the objective compound [I] can be carried out by using any    conventional method for coupling thiol with halogenated aryl,    halogenated heteroaryl, aryl triflate or heteroaryl triflate. For    example, the preparation can be preferably carried out by treating    the compound having the corresponding haloaryl with thiol    (hydroxyalkylthiol, dialkylaminoalkylthiol, or the like) in the    presence of a metal catalyst (tetrakis(triphenylphosphine)palladium    or the like) in an appropriate solvent (dioxane, toluene, THF,    1,2-dimethoxyethane or the like, or a mixed solvent thereof) in the    presence or absence of a base (triethylamine, diisopropylamine or    the like) at 0° C. to 200° C.-   (DD) The preparation of the compound having mono-substituted or    di-substituted alkylamino on R¹-R⁶ among the objective compound [I]    can be preferably carried out by, for example, treating the compound    having the corresponding haloalkyl with mono-substituted or    di-substituted alkylamine (dimethylamine, diethylamine, methylamine    or the like) in an appropriate solvent (methanol, ethanol, dioxane,    toluene, THF, 1,2-dimethoxyethane or the like) in the presence or    absence of a base (triethylamine, diisopropylamine or the like) at    0° C. to 200° C. Also, the compound having dimethylamino can be    preferably prepared by treating the compound having the    corresponding haloalkyl with N-(trimethyl-silyl)dimethylamine in an    appropriate solvent (methanol, ethanol, dioxane, toluene, THF,    1,2-dimethoxyethane or the like) at 0° C. to 200° C.-   (EE) The preparation of the compound having alkynyl on R¹, R², R⁵ or    R⁶ among the objective compound [I] can be carried out by using any    conventional method of so-called Sonogashira coupling reaction of    halogenated aryl, halogenated heteroaryl, aryl triflate or    heteroaryl triflate with the compound having alkyne. For example,    the preparation can be preferably carried out by treating the    compound having the corresponding halogen with alkyne (propargyl    alcohol, N,N-dimethylpropargylamine or the like) in the presence of    a metal catalyst (tetrakis(triphenylphosphine)palladium or the like)    in an appropriate solvent (dioxane, toluene, THF,    1,2-dimethoxyethane or the like) in the presence or absence of a    base (triethylamine, diisopropylamine or the like) and/or copper    salt (for example, cuprous iodide) at 0° C. to 200° C.-   (FF) The preparation of the compound having tetrazolyl on R¹-R⁶    among the objective compound [I] can be carried out by using any    conventional method for converting cyano group into tetrazolyl    group. For example, the preparation can be preferably carried out by    treating the compound having the corresponding cyano with metal    azide (sodium azide, tributyltin azide, trimethylsilyl azide) in an    appropriate solvent (methanol, ethanol, DMF, dioxane, toluene, THF,    1,2-dimethoxyethane or the like) in the presence or absence of a    base (triethylamine, diisopropylamine or the like) or a salt    (triethylamine hydrochloride or the like) at 0° C. to 200° C.-   (GG) The preparation of the compound having    O-alkoxycarbonylhydroxyimine on R¹-R⁶ among the objective compound    [I] can be preferably carried out by treating the compound having    the corresponding hydroxyimine with alkyl chlorocarbonate (ethyl    chlorocarbonate or the like) in an appropriate solvent (DMF,    dioxane, toluene, THF, 1,2-dimethoxyethane or the like) or as neat    in the presence or absence of a base (pyridine, triethylamine or the    like) at 0° C. to 200° C.-   (HH) The preparation of the compound having aryl or heteroaryl on    R¹, R², R⁵ or R⁶ among the objective compound [I] can be carried out    by using any conventional method of so-called Stille coupling or    Suzuki coupling reaction. For example, the preparation can be    preferably carried out by treating the compound having the    corresponding haloaryl with aryltrialkyltin, heteroaryltrialkyltin,    aryldihydroxyborane, heteroaryldihydroxyborane, arylcatecholborane,    heteroarylcatecholborane or the like in the presence of a metal    catalyst (for example, dichlorobis(triphenylphosphine)palladium,    tetrakis-(triphenylphosphine)palladium,    tris(dibenzylideneacetone)dipalladium,    dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium, palladium    acetate or the like) in an appropriate solvent (dioxane, toluene,    THF, 1,2-dimethoxyethane or the like, or a mixed solvent thereof) in    the presence or absence of a base (triethylamine, diisopropylamine,    sodium tert-butoxide, sodium carbonate, cesium carbonate, potassium    phosphate or the like) at 0° C. to 200° C.-   (II) In the above each reaction, a protecting group can be    optionally introduced or removed to give the desired compound [I]    finally. The method for introduction and removal of the protecting    group can be carried out according to the description of Protective    Groups in Organic Synthesis Third Edition (Theodora W. Green and    Peter G. Wuts).-   (JJ) Alternatively, the compound [I] can be also synthesized by    optionally carrying out any of the above reaction of (A) to (II) in    the compound [II] to the compound [XIII] in an appropriate stage in    each process of (1) to (13).

Example of Experiment

A Glucokinase Activation Effect

(Method)

A glucokinase activity was examined by measuring the amount of NADPHobtained in generating 6-phosphogluconic acid from glucose-6-phosphoricacid by a coupling enzyme glucose-6-phosphate dehydrogenase not bymeasuring directly the produced glucose-6-phosphoric acid. Theglucokinase enzyme used in the examination is human-liver type GST-GKexpressed in E. Coli. The measurement of GK activity was carried out bythe following procedures.

Twenty five mM HEPES buffer (pH7.4) containing 25 mM MgCl₂, mM KCl, 1 mMDTT, 5 mM NADP (Roche), 16.64 μg/mL G6PDH (Roche 737-232 grade II fromyeast) and 2.8 μg/mL GST-GK was prepared as a reaction solution. Anevaluating compound dissolved in DMSO was added to the reaction solutionto give final concentration of 0.001 to 100 μM (5% DMSO). Thereto wasadded glucose (final concentration of 5 mM) as a substrate and was addedATP (final concentration of 5 mM), and the reaction was started. Thereaction temperature is 30° C. and a generation of NADPH was monitoredby changes of absorbance of 340 nm. An increasing in absorbance for 15minutes from starting reaction was measured and the blank-correctedvalue was used as GK activity (mOD/min). EC₅₀ level was calculated by aGK activity level in at each concentration of an evaluating compound.

(Results)

EXAMPLE No. EC₅₀ (μM)  6 1.20  9 0.55 10 0.79 11 0.88 13-3  0.17 18-2 0.93 24-25 0.084 46-1  0.10 56 0.32 62-5  0.41 62-10 0.27 67-2  0.3982-22 0.26 82-78 0.60 84-12 0.41 91-8  0.52 94-6  0.51 98-1  0.84 98-7 0.23 104-2  0.30 116  0.57 139-125 0.76 139-244 0.46 139-134 0.18139-94  0.35 139-237 0.60 139-41  0.54 139-159 0.52 139-182 0.52 139-2140.57 139-221 0.13

Another objective of the present invention is to provide an industriallyadvantageous method for preparing 5-substituted 2-aminothiazole and asalt thereof, and it has surprisingly been found that the desired5-substituted 2-aminothiazole compound can be prepared in high yield byusing 2-aminothiazole wherein the 5-position is not substituted as astarting material. The method of the present invention is anindustrially very advantageous since the starting material,2-aminothiazole, is commercially available at a low cost compared to5-bromo-2-aminothiazole, which gives lowering of the production cost,and further various substituents can be introduced at 5-position of2-aminothiazole.

Thus, the present invention includes the following embodiments of themethod for preparing the desired compounds:

-   [1] A method for preparing 5-substituted 2-aminothiazole of the    general formula:

wherein the symbols have the same meanings as mentioned above, or a saltthereof by treating 2-aminothiazole wherein the amino group may beprotected, or a salt thereof with a base, followed by treating theresultant with an electrophile of the general formula:G-X  [XXII]wherein X is a leaving group, G is halogen atom, formyl, alkoxycarbonyl,alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, dialkylsulforyl,alkylboryl or trialkylsilyl;and removing the protecting group where the amino group is protected.

-   [2] A method for preparing of [1] wherein 2-amino-1,3-thiazole    wherein the amino group may be protected is 2-amino-1,3-thiazole    wherein the amino group is protected.-   [3] A method for preparing of [1] or [2] wherein G is halogen atom    or formyl.-   [4] A method for preparing of [1], [2] or [3] wherein the base is    alkyl lithium.-   [5] A method for preparing of [1], [2], [3] or [4] wherein the base    is used in two or more equivalents to one equivalent of    2-amino-1,3-thiazole or a salt thereof.

5-Substituted 2-aminothiazole or a salt thereof to be prepared by themethod of the present invention is preferably a compound wherein thesubstituent G is halogen atom or formyl. A compound wherein G isfluorine atom or formyl, particularly fluorine atom, is more preferable.

A conventional protecting group can be used as a protecting group of theamino group of the starting material, 2-aminothiazole. Said protectinggroup includes, for example, oxycarbonyl-type protecting group such assubstituted or unsubstituted alkoxycarbonyl (for example,methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl,tert-butoxycarbonyl), substituted or unsubstituted aralkyloxycarbonyl(for example, benzyloxycarbonyl), or substituted or unsubstitutedaryloxycarbonyl (for example, phenoxycarbonyl); formyl; carbonyl-typeprotecting group such as substituted or unsubstituted alkanoyl (forexample, trifluoroacetyl, tert-butanoyl), or substituted orunsubstituted arylcarbonyl (for example, benzoyl); or alkyl-typeprotecting group such as substituted or unsubstituted alkyl (forexample, tert-butyl), or substituted or unsubstituted aralkyl (forexample, benzyl, benzhydryl, trityl).

A preferable protecting group among them is oxycarbonyl-type protectinggroup, carbonyl-type protecting group, alkyl-type protecting group, morepreferably oxycarbonyl-type protecting group, carbonyl-type protectinggroup, particularly oxycarbonyl-type protecting group.

A preferable oxycarbonyl-type protecting group is substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedaralkyloxycarbonyl, particularly substituted or unsubstitutedalkoxycarbonyl. A preferable carbonyl-type protecting group issubstituted or unsubstituted alkanoyl. A preferable alkyl-typeprotecting group is substituted or unsubstituted aralkyl.

A preferable substituted or unsubstituted alkoxycarbonyl istert-butoxycarbonyl. A preferable substituted or unsubstitutedaralkyloxycarbonyl is benzyloxycarbonyl. A preferable substituted orunsubstituted alkanoyl is trifluoroacetyl. A preferable substituted orunsubstituted aralkyl is benzhydryl.

A salt of 2-aminothiazole wherein the amino group may be protectedincludes a salt with an inorganic acid such as hydrochloride,hydrobromide, hydroiodide, sulfate, nitrate or phosphate; or a salt withan organic acid such as formate, acetate, propionate, oxalate, malonate,succinate, fumarate, maleate, lactate, malate, tartarate, citrate,methanesulfonate, ethanesulfonate, benzenesulfonate or toluenesulfonate.

A strong base can be preferably used as a base of base-treatment. Such astrong base includes lithium compound such as alkyllithium,cycloalkyllithium, aryllithium, lithium amide or lithium cyclyl-amide.Among them, using alkyllithium or cycloalkyllithium is preferable, mostpreferably alkyllithium in particular.

Alkyllithium includes n-butyllithium, tert-butyllithium,sec-butyllithium or the like. Cycloalkyllithium includescyclohexyllithium or the like. Aryllithium includes phenyllithium or thelike. Lithium amide includes lithium dialkylamide (lithiumdiisopropylamide), lithium bis(trialkylsilyl)amide (lithiumbis(trimethylsilyl)amide) or the like. Lithium cyclyl-amide includeslithium 2,2,6,6-tetraalkylpiperidide (lithium2,2,6,6-tetramethylpiperidide) or the like.

The base-treatment can be carried out in an appropriate solvent undercooling. Any of aliphatic hydrocarbon-type solvent, aromatichydrocarbon-type solvent, ether-type solvent, phosphoric amide-typesolvent, urea-type solvent, amine-type solvent or a mixed solventthereof can be preferably used as said solvent. A preferable solventamong them is ether-type solvent.

The aliphatic hydrocarbon-type solvent includes pentane, hexane,cyclohexane, preferably hexane or cyclohexane. The aromatichydrocarbon-type solvent includes toluene, xylene, preferably toluene.The ether-type solvent includes anisole, dimethyl ether, diethyl ether,diisopropyl ether, tert-butylmethyl ether, cyclopentyl methyl ether,THF, 1,2-dimethoxyethane, preferably diethyl ether, THF,1,2-dimethoxyethane, particularly THF. The phosphoric amide-type solventincludes hexaalkylphosphoric triamide, preferably hexamethyl-phosphorictriamide in particular. The urea-type solvent includesN,N′-dimethylpropyleneurea, N,N′-dimethylethyleneurea, preferablyN,N′-dimethylpropyleneurea in particular. The amine-type solventincludes N,N,N′,N′-tetramethylethylenediamine or the like.

The proceeding of the reaction can be promoted by adding a small portionof the phosphoric amide-type solvent, the urea-type solvent or theamine-type solvent as a co-solvent to the other solvent. For example,the co-solvent including hexamethylphosphoric triamide,N,N′-dimethylpropyleneurea, N,N′-dimethylethyleneurea orN,N,N′,N′-tetramethylethylene diamine, or a mixed solvent comprising oneor more kinds of these solvents can be added to the solvent includingpentane, hexane, cyclohexane, toluene, xylene, anisole, dimethyl ether,diethyl ether, diisopropyl ether, tert-butylmethyl ether, cyclopentylmethyl ether, THF or 1,2-dimethoxyethane, or a mixed solvent comprisingone or more kinds of these solvents. An amount of the co-solvent addedin using in this way includes a range of 0.1% to 70%, preferably a rangeof 3% to 30% to an original solvent. In this case, the preferableoriginal solvent among the above-mentioned is hexane, cyclohexane,toluene, diethyl ether, tert-butylmethyl ether, THF or1,2-dimethoxyethane, or a mixed solvent comprising one or more kinds ofthese solvents, particularly hexane, toluene, diethyl ether, THF or1,2-dimethoxyethane, or a mixed solvent comprising one or more kinds ofthese solvents. The most preferable one is THF.

The cooling condition in base-treatment includes a range of −100° C. to25° C., preferably a range of −78° C. to 25° C. Particularly, a range of−78° C. to 0° C. is preferred.

The proceeding of the reaction can be promoted by using greater or equalto two equivalents of a base to one equivalent of 2-aminothiazole or asalt thereof in base-treatment.

An electrophile using in electrophile-treatment can include anelectrophile of the general formula:G-X  [XXII]wherein the symbols have the same meanings as mentioned above.

Any conventional leaving group can be preferably used as X of theelectrophile G-X. Therefore, G-X can be, for example, halide-typeelectrophile using halogen atom as X, ester-type electrophile usingalkoxy or the like as X, or amine-type electrophile using substituted orunsubstituted amino group as X. Also, in case that G is halogen atom oralkylthio, G-X can be dimer-type electrophile of G (in case X=G). Amongthem, amine-type electrophile is preferred.

The halide-type electrophile includes alkyl halocarbonate (ethylchlorocarbonate, methyl chlorocarbonate or the like), alkylphosphorylhalide (ethylphosphoryl chloride or the like), trialkylsilyl halide(trialkylsilyl chloride, trialkylsilyl bromide or the like), alkylthiohalide (methylthio chloride or the like), alkylsulfinyl halide(methylsulfinyl chloride or the like), or alkylsulfonyl chloride(methanesulfonyl chloride, ethanesulfonyl chloride or the like). Amongthem, alkylphosphoryl halide or trialkylsilyl halide is preferred,particularly ethylphosphoryl chloride or trimethylsilyl chloride is mostpreferred. The ester-type electrophile includes dialkyl carbonate(diethyl carbonate, dimethyl carbonate or the like) or trialkyl borate(trimethyl borate, triisopropyl borate or the like). Among them,trialkyl borate is preferred, particularly trimethyl borate is mostpreferred. The amine-type electrophile includes N-chlorosuccinimide,N-bromosuccinimide, N-iodosuccinimide, N-fluoropyridinium,1-fluoropyridin-2-one, N-fluoro-quinuclidium,1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebistetrafluoroborate, N-fluoroperfluoropiperidine,N-fluorobenzene-sulfonylimide, N-fluorotrifluoromethanesulfonylimide,N-fluoro-N-methyl-p-toluenesulfonylamide or2,3-dihydro-3,3-dimethyl-2-fluoro-1,2-benzothiazole-1,1-dione. Amongthem, N-fluorobenzenesulfonyl-imide orN-fluoro-N-methyl-p-toluenesulfonylamide is preferred, particularlyN-fluorobenzenesulfonylimide is most preferred. The dimer-typeelectrophile includes dialkyl disulfide (dimethyl disulfide,bis(trifluoromethyl)disulfide or the like) or halogen molecule(fluorine, chlorine, bromine or iodine). Among them, dialkyl disulfideis preferred, particularly dimethyl disulfide is most preferred.

The electrophile-treatment can be carried out in an appropriate solventunder cooling. The solvent can preferably include the solvent of theabove-mentioned in the base-treatment.

The base-treatment and the electrophile-treatment can be carried out inthe same solvent by selecting an appropriate solvent. In this case, theelectrophile-treatment can be carried out sequentially in the solventused in the base-treatment. Such a solvent includes a mixed solvent ofTHF and hexane, a mixed solvent of diethyl ether and hexane, or thelike.

The cooling condition of the electrophile-treatment includes a range of−100° C. to 25° C., preferably a range of −78° C. to 25° C.

The protecting group which protects the amino group of 5-substituted2-aminothiazole compound or a salt thereof can be removed by theconventional method. A removing method of such a protecting groupincludes, for example, acidolysis, acid hydrolysis, alkali hydrolysis,catalytic reduction or the like.

The acidolysis can be carried out by using an acid such astrifluoroacetic acid, hydrochloric acid, sulfuric acid, titaniumtetrachloride or stannic chloride in an appropriate solvent (forexample, methylene chloride, chloroform, toluene, methanol, ethanol,THF, water or the like). The acid hydrolysis can be carried out by usingan acid such as hydrochloric acid or sulfuric acid in an appropriatesolvent (for example, water, or a mixed solvent of methanol, ethanol,THF or the like with water). Also, the alkali hydrolysis can be carriedout by using sodium hydroxide, potassium hydroxide, potassium carbonate,sodium carbonate, sodium bicarbonate or the like in a solvent such aswater, methanol, ethanol or THF.

The resulting 5-substituted 2-aminothiazole compound or a salt thereofcan be the desired salt by the conventional method. The salt of5-substituted 2-aminothiazole compound includes a salt with an inorganicacid such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate,phosphate; or a salt with an organic acid such as formate, acetate,propionate, oxalate, malonate, succinate, fumarate, maleate, lactate,malate, tartarate, citrate, methanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate. Moreover, in case that substitutentat 5-position has an acidic group, the salt includes a salt with aninorganic base such as alkali metal including lithium, sodium orpotassium, alkali earth metal including calcium or magnesium, or othermetal including zinc or aluminum; or a salt with an organic base such asammonium, choline, diethanolamine, lysine, ethylenediamine,tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane,N-methylglucosamine, triethanolamine or dehydroabiethylamine.

In the above method for preparing of the present invention, aryl andaryl in aralkyl include monocyclic, bicyclic or tricyclic aryl having 6to 14 carbons, preferably 6 to 10 carbons, specifically phenyl,naphthyl, phenanthryl, anthranyl or the like. Alkyl, alkoxy, alkanoyl,aryl or aralkyl may be substituted with one or more groups selected fromhalogen atom, alkyl, alkoxy or aryl.

The other groups are the same as the above-mentioned in the oximederivative [I].

Meanwhile, thiazole includes 1,2-thiazole (isothiazole) and1,3-thiazole, but in the above method for preparing of the presentinvention, it is described simply as “thiazole” in the meaning of1,3-thiazole.

In the present specification, DMF represents N,N-dimethylformamide andTHF represents tetrahydrofuran.

EFFECT OF THE INVENTION

The compound [I] of the present invention or a pharmaceuticallyacceptable salt thereof is useful for preventing or treating diseasesinvolving glucokinase, for example, diabetes, particularly type 2diabetes, or chronic complications associated with diabetes such asretinopathy, nephropathy, neuropathy, ischemic heart disease orarteriosclerosis, additionally obesity, because of its excellentglucokinase activation effect.

On the other hand, 5-substituted 2-aminothiazole compound or a saltthereof can be prepared in a good yield by the method for the preparingof the present invention. Also, the method for the preparing of thepresent invention is an industrially advantageous method which canintroduce various substituents at 5-position of 2-aminothiazoledepending on the kinds of the electrophile used. Additionally, it is anindustrially very advantageous method because 2-aminothiazole, thestarting material of the method of the present invention, is low inprice compared to 5-bromo-2-aminothiazole, which gives lowering ofproduction cost.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained in more detail in the followingEXAMPLES and REFERENCE EXAMPLES, but the invention is not limited tothese explanations.

In EXAMPLES, APCI is atmospheric pressure chemical ionization massspectrum and ESI is electrospray ionization mass spectrum.

EXAMPLES Example 1

-   (1) To a solution of aluminum chloride (67.0 g, 503 mmol) in    methylene chloride (380 ml) was added methyl chloroglyoxylate (48.9    g, 399 mmol) under ice-cooling, and the mixture was stirred for 30    minutes at the same temperature. To the mixture was added a solution    of cyclopropyl phenyl sulfide (compound 1-A) (50 g, 333 mmol) in    methylene chloride (60 ml), and then the ice-cooling bath was    removed and the mixture was stirred at room temperature for 1.5    hours. The reaction mixture was poured onto ice, and then the    methylene chloride layer was separated and concentrated in vacuo.    The residue was dissolved in ethyl acetate and then washed    sequentially with water, a saturated aqueous sodium bicarbonate    solution and brine, followed by drying over sodium sulfate and    concentrated in vacuo. The residue was recrystallized from hexane to    give the compound (1-B) (69.5 g, yield 88%) as pale yellow crystals.-   (2) To a solution of the above compound (57.0 g, 241 mmol) in    methanol-THF (1:1) (1480 ml) was added dropwise an aqueous solution    (513 ml) of Oxone™ (177.9 g, 289 mmol) under ice-cooling over 1    hour, and then the mixture was stirred at room temperature for 12    hours after removing the ice bath. The insoluble materials were    filtered off, and then the filtrate was concentrated in vacuo. The    residue was dissolved in ethyl acetate, washed sequentially with    water and brine, dried over sodium sulfate and concentrated in    vacuo. The resulting residue was recrystallized from diethyl ether    to give the compound (1-C) (44.3 g, yield 69%) as pale yellow    crystals.-   (3) To a solution of the above compound (65.0 g, 242 mmol) in    methanol (450 ml) was added hydroxylamine hydrochloride (23.6 g, 339    mmol) at room temperature, and the mixture was heated to reflux for    3 hours. The reaction mixture was concentrated in vacuo and then the    residue was dissolved in ethyl acetate and washed sequentially with    water and brine, followed by drying over sodium sulfate and    concentrated in vacuo. The residue was dissolved in trifluoroacetic    acid (200 ml) and the mixture was stirred at room temperature for 12    hours. After concentration in vacuo, the residue was recrystallized    from hexane-ethyl acetate to give the compound (1-D) (53.1 g, yield    78%) as colorless crystals.-   (4)-   (4-1) To a solution of the above compound (37.2 g, 130 mmol),    triphenylphosphine (47.7 g, 182 mmol) and    (S)-3-hydroxytetrahydrofuran (26.0 g, 294 mmol) in THF (400 ml) was    added dropwise diisopropyl azodicarboxylate (36.8 g, 182 mmol) under    ice-cooling, and the mixture was stirred at the same temperature for    3 hours and at room temperature for another 16 hours. The reaction    mixture was ice-cooled again, and thereto were added water (55 ml)    and a 5.4N sodium hydroxide solution (36 ml). The mixture was    stirred at the same temperature for 1 hour and concentrated. Thereto    was added water, and the mixture was washed with ethyl acetate twice    and then the aqueous layer was acidified with 10% hydrochloric acid    to pH 2 to 3 and extracted with chloroform. The organic layer was    separated, followed by washing sequentially with water and brine and    drying over sodium sulfate, and concentrated in vacuo. The residue    was recrystallized from ethyl acetate to give the compound (1-E)    (31.6 g, yield 72%) as colorless crystals.-   (4-2) The above compound (1-E) was also synthesized by using the    following alternative method.-   (4-2-1) To a solution of the compound (1-D) (68.1 g, 241 mmol) and    potassium carbonate (66.5 g, 482 mmol) in DMF (1200 ml) was added    (S)-3-tetrahydrofuranol p-toluenesulfonate (synthesized from    (S)-3-hydroxytetrahydrofuran and p-toluenesulfonyl chloride) (69.9    g, 289 mmol) under ice-cooling, and the ice bath was removed. The    mixture was stirred at room temperature overnight, and then diluted    with ethyl acetate, washed sequentially with water and brine, dried    over sodium sulfate and concentrated in vacuo to give the compound    (1-D-1) (94.7 g, quantitatively).-   (4-2-2) To a solution of the above compound (94.7 g) in    water-methanol (1:3.3) (365 ml) was added an aqueous solution    (55 ml) of sodium hydroxide (12.5 g, 312 mmol) under ice-cooling,    and the mixture was stirred at the same temperature for 30 minutes.    To the reaction mixture was added ethyl acetate, and the aqueous    layer was separated and then acidified with 10% hydrochloric acid    and extracted with chloroform. The organic layer was separated and    then washed sequentially with water and brine, dried over sodium    sulfate and concentrated in vacuo to give the compound (1-E) (58.5    g, yield 71%).-   (5) To a solution of the compound (1-E) (41.9 g, 123 mmol),    2-amino-5-formylthiazole hydrochloride (30.4 g, 184 mmol) and    N,N-dimethylaminopyridine (22.5 g, 184 mmol) in methylene chloride    (1270 ml) was added dropwise    N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide (28.6 g, 184 mmol)    at room temperature. The mixture was stirred at the same temperature    for 12 hours and concentrated in vacuo. The residue was purified by    silica gel column chromatography (3% methanol-chloroform) to give    the compound (1-F) (33.6 g, yield 61%) as pale yellow crystals.

MS (m/z) APCI: 450 [M+H]⁺

Example 2

To a solution of the compound (1-F) (200 mg, 0.44 mmol) and(R)-2-methylpiperazine (223 mg, 2.65 mmol) in methylene chloride (4 ml)was added sodium triacetoxyborohydride (112 mg, 0.55 mmol) underice-cooling, and the mixture was stirred at room temperature for 24hours. To the reaction solution was added water, and the organic layerwas separated, dried over magnesium sulfate and concentrated in vacuo.The residue was puridied by silica gel column chromatography (NH-silicagel; 1 to 6% methanol-chloroform) to give the compound (2-A) (116.7 mg,yield 49%) as colorless crystals.

MS (m/z) APCI: 534 [M+H]⁺

Examples 3 to 10

Corresponding starting compounds were treated in the similar manner asEXAMPLE 2 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 3

534 APCI[M + H]⁺ 4

548 APCI[M + H]⁺ 5

548 APCI[M + H]⁺ 6

534 APCI[M + H]⁺ 7

534 APCI[M + H]⁺ 8

606 APCI[M + H]⁺ 9

576 APCI[M + H]⁺ 10

562 APCI[M + H]⁺

Example 11

To a solution of the compound of EXAMPLE 4 (30 mg, 0.055 mmol) anddiisopropylethylamine (21 mg, 0.165 mmol) in chloroform (1.5 ml) wasadded methoxyacetyl chloride (9.0 mg, 0.083 mmol) under ice-cooling, andthe mixture was stirred at room temperature for 24 hours. To thereaction mixture was added an aqueous sodium bicarbonate solution. Theorganic layer was separated and concentrated in vacuo. The residue waspurified by LC/MS (Xterra Prep MS C18 5 μm, 30×50 mm; MeOH-10 mM(NH₄)₂CO₃aq, 40:60 to 70:30) to give the above compound (13 mg, yield43%) as colorless crystals.

MS (m/z) ESI: 620 [M+H]⁺

Example 12

-   (1) An enantiomer ((S)-isomer) of the compound (1-E) was synthesized    by reacting in the similar manner as EXAMPLE 1-(4) using the    corresponding antipode ((R)-isomer) as an alternative to    (S)-3-hydroxytetrahydrofuranol used in EXAMPLE 1-(4) or a tosylate    thereof.-   (2) The titled compound was obtained by reacting the above compound    in the similar manner as EXAMPLE 1-(5).

MS (m/z) APCI: 440 [M+H]⁺

Example 13

Corresponding starting compounds were reacted in the similar manner asEXAMPLE 1-(5) to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 13 1

489 APCI[M + H]⁺ 13 2

466 APCI[M + H]⁺ 13 3

560 APCI[M + H]⁺ 13 4

603 APCI[M + H]⁺ 13 5

546 APCI[M + H]⁺ 13 6

560 APCI[M + H]⁺ 13 7

574 APCI[M + H]⁺ 13 8

646 APCI[M + H]⁺ 13 9

632 APCI[M + H]⁺

Example 14

The compound of EXAMPLE 13-(4) (2.69 g, 4.46 mmol) was dissolved informic acid (50 ml). The mixture was stirred at room temperature for 20hours and concentrated in vacuo. The residue was chased with toluene andsolidified with ethyl acetate-hexane to give the above compound (2.46 g,quantitatively).

MS (m/z) ESI: 545 [M−H]⁻

Example 15

To a suspension of the compound of EXAMPLE 13-(8) (151 mg, 0.234 mmol)in ethyl acetate (3 ml) was added a 4M hydrogen chloride solution indioxane (6 ml, 24 mmol) at room temperature. The mixture was stirred for16 hours at the same temperature and then diluted with diethyl ether.The precipitated crystals were collected and dried to give the abovecompound (127 mg, yield 93%).

MS (m/z) APCI: 546 [M+H]⁺

Example 16

The compound of EXAMPLE 13-(9) was treated in the similar manner asEXAMPLE 15 to give the above compound.

MS (m/z) APCI: 532 [M+H]⁺

Example 17

To a solution of the carboxylic acid (1-E) of EXAMPLE 1 (100 mg, 0.295mmol) and the amine of REFERENCE EXAMPLE 8 (68.5 mg, 0.324 mmol) inTHF-N-methylpyrrolidone (1:1) (6 ml) was added4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride(hereinafter called DMT-MM) (90 mg, 0.325 mmol) at room temperature. Themixture was stirred for 20 hours at the same temperature and dilutedwith diisopropyl ether-hexane. The resulting precipitates were collectedand purified by LC/MS (Xterra Prep MS C18 5 μm, 30×50 mm; MeOH-10 mM(NH₄)₂CO₃aq, 70:30) to give the above compound (8 mg, yield 6%) ascolorless crystals.

MS (m/z) APCI: 533 [M+H]⁺

Example 18

Corresponding starting compounds were treated in the similar manner asEXAMPLE 2 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 18 1

537 APCI[M + H]⁺ 18 2

521 APCI[M + H]⁺ 18 3

548 APCI[M + H]⁺ 18 4

553 APCI[M + H]⁺ 18 5

569 APCI[M + H]⁺ 18 6

588 APCI[M + H]⁺ 18 7

562 APCI[M + H]⁺ 18 8

562 APCI[M + H]⁺ 18 9

606 APCI[M + H]⁺ 18 10

507 APCI[M + H]⁺ 18 11

626 APCI[M + H]⁺ 18 12

634 APCI[M + H]⁺ 18 13

576 APCI[M + H]⁺ 18 14

548 APCI[M + H]⁺ 18 15

550 APCI[M + H]⁺ 18 16

536 APCI[M + H]⁺ 18 17

522 APCI[M + H]⁺ 18 18

548 APCI[M + H]⁺ 18 19

576 APCI[M + H]⁺ 18 20

523 APCI[M + H]⁺ 18 21

536 APCI[M + H]⁺ 18 22

550 APCI[M + H]⁺ 18 23

567 APCI[M + H]⁺ 18 24

537 APCI[M + H]⁺ 18 25

548 APCI[M + H]⁺ 18 26

523 APCI[M + H]⁺ 18 27

562 APCI[M + H]⁺ 18 28

564 APCI[M + H]⁺ 18 29

598 APCI[M + H]⁺ 18 30

612 APCI[M + H]⁺ 18 31

626 APCI[M + H]⁺ 18 32

597 APCI[M + H]⁺ 18 33

598 APCI[M + H]⁺ 18 34

597 APCI[M + H]⁺ 18 35

606 APCI[M + H]⁺ 18 36

560 APCI[M + H]⁺ 18 37

548 APCI[M + H]⁺ 18 38

563 APCI[M + H]⁺ 18 39

479 APCI[M + H]⁺

Example 19

Corresponding starting compounds were treated in the similar manner asEXAMPLE 11 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 19 1

592 ESI+/UV[M + H]⁺ 19 2

576 ESI+/UV[M + H]⁺ 19 3

606 ESI+/UV[M + H]⁺ 19 4

590 ESI+/UV[M + H]⁺ 19 5

590 ESI+/UV[M + H]⁺ 19 6

620 ESI+/UV[M + H]⁺ 19 7

634 APCI[M + H]⁺ 19 8

576 APCI[M + H]⁺ 19 9

606 APCI[M + H]⁺ 19 10

592 APCI[M + H]⁺ 19 11

576 APCI[M + H]⁺ 19 12

606 APCI[M + H]⁺ 19 13

592 APCI[M + H]⁺ 19 14

606 APCI[M + H]⁺ 19 15

592 APCI[M + H]⁺ 19 16

606 APCI[M + H]⁺ 19 17

604 APCI[M + H]⁺ 19 18

590 APCI[M + H]⁺ 19 19

606 APCI[M + H]⁺ 19 20

604 APCI[M + H]⁺ 19 21

620 APCI[M + H]⁺ 19 22

626 APCI[M + H]⁺ 19 23

602 APCI[M + H]⁺ 19 24

612 APCI[M + H]⁺ 19 25

641 APCI[M + H]⁺ 19 26

619 APCI[M + H]⁺ 19 27

630 APCI[M + H]⁺ 19 28

602 APCI[M + H]⁺ 19 29

592 APCI[M + H]⁺ 19 30

605 APCI[M + H]⁺

Example 20

The compound of EXAMPLE (18-12) (640 mg, 1.01 mmol) was dissolved informic acid (10 ml). The mixture was stirred at room temperature for 24hours, concentrated, neutralized with a saturated aqueous sodiumcarbonate solution and extracted with methylene chloride. The organiclayer was washed sequentially with water and brine, dried over magnesiumsulfate and concentrated in vacuo. The residue was purified by NH-silicagel column chromatography (5% methanol-chloroform) to give the abovecompound (385 mg, yield 72%) as a colorless solid.

MS (m/z) APCI: 534 [M+H]⁺

Corresponding starting compounds were converted in the similar manner asEXAMPLE 2 to the corresponding compounds having a tert-butoxycarbonylgroup, and then the resulting starting compounds were treated in thesimilar manner as the above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 20 1

534 APCI[M + H]⁺ 20 2

534 APCI[M + H]⁺ 20 3

534 APCI[M + H]⁺ *The compound (20-3) was isolated as a dihydrochloridesalt.

Example 21

The compound of EXAMPLE 19-(7) (2.7 g, 4.26 mmol) was dissolved inmethanol (30 ml), and thereto was added potassium carbonate (600 mg,4.26 mmol) at room temperature. The mixture was stirred at roomtemperature for 4 hours and concentrated, and thereto was added water.The mixture was extracted with ethyl acetate, and the organic layer waswashed sequentially with water and brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (1.5 to 10% methanol-ethyl acetate) to give the abovecompound (1.7 g, yield 68%) as a colorless solid.

MS (m/z) APCI: 592 [M+H]⁺

Example 22

A solution of the compound of EXAMPLE 3 (80 mg, 0.15 mmol),difluoroacetic acid (0.028 ml, 0.45 mmol) andN-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (116 mg,0.60 mmol) in chloroform (3 ml) was stirred at room temperature for 7hours. The reaction mixture was poured into a saturated aqueous sodiumbicarbonate solution and the mixture was extracted with ethyl acetate.The organic layer was dried over sodium sulfate, concentrated in vacuo,and the residue was purified by silica gel chromatography (0 to 5%methanol-chloroform) to give the above compound (85.6 mg, yield 93%) asa colorless solid.

MS (m/z) APCI: 612 [M+H]⁺

Corresponding compounds were reacted in the similar manner as theabove-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 22 1

620 APCI[M + H]⁺ 22 2

646 APCI[M + H]⁺ 22 3

646 APCI[M + H]⁺

Example 23

The compound of EXAMPLE 3 (80 mg, 0.13 mmol) was dissolved in ethylformate (3 ml), and the mixture was heated to reflux for 32 hours. Thereaction mixture was concentrated and the residue was purified by silicagel column chromatography (0 to 8% methanol-chloroform) to give theabove compound (72.4 mg, yield 98%) as a colorless solid.

MS (m/z) APCI: 562 [M+H]⁺

Corresponding starting compounds were reacted in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 23 1

562 APCI[M + H]⁺ 23 2

562 APCI[M + H]⁺ 23 3

562 APCI[M + H]⁺ 23 4

562 APCI[M + H]⁺

Example 24

Corresponding starting compounds were treated in the similar manner asEXAMPLE 1-(5) to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 24 1

440 APCI[M + H]⁺ 24 2

456/458 APCI[M + H]⁺ 24 3

436 APCI[M + H]⁺ 24 4

529 APCI[M + H]⁺ 24 5

423 APCI[M + H]⁺ 24 6

437 APCI[M + H]⁺ 24 7

416 APCI[M + H]⁺ 24 8

450/452 APCI[M + H]⁺ 24 9

417 APCI[M + H]⁺ 24 10

495/497 APCI[M + H]⁺ 24 11

507/509 APCI[M + H]⁺ 24 12

468 APCI[M + H]⁺ 24 13

447 APCI[M + H]⁺ 24 14

508 APCI[M + H]⁺ 24 15

584 APCI[M + H]⁺ 24 16

467 APCI[M + H]⁺ 24 17

472 APCI[M + H]⁺ 24 18

517 APCI[M + H]⁺ 24 19

502 APCI[M + H]⁺ 24 20

494/496 APCI[M + H]⁺ 24 21

430 APCI[M + H]⁺ 24 22

500/502 APCI[M + H]⁺ 24 23

490 APCI[M + H]⁺ 24 24

463 APCI[M + H]⁺ 24 25

503 APCI[M + H]⁺ 24 26

441 APCI[M + H]⁺ 24 27

469 APCI[M + H]⁺ 24 28

490 APCI[M + H]⁺ 24 29

434 APCI[M + H]⁺ 24 30

473 APCI[M + H]⁺ 24 31

494 APCI[M + H]⁺ 24 32

474 APCI[M + H]⁺ 24 33

451 APCI[M + NH₄]⁺ 24 34

521 APCI[M + H]⁺ 24 35

507 APCI[M + H]⁺ 24 36

443 APCI[M + H]⁺ 24 37

451 APCI[M + H]⁺ 24 38

465 APCI[M + H]⁺ 24 39

457 APCI[M + H]⁺ 24 40

647 APCI[M + H]⁺ 24 41

471 APCI[M + H]⁺ 24 42

463 APCI[M + H]⁺ 24 43

522 APCI[M + NH₄]⁺ 24 44

466 APCI[M + H]⁺

Example 25

-   (1) To a solution of N-hydroxyphthalimide (142 g, 868 mmol),    triphenylphosphine (252.9 g, 964 mmol) and    (S)-3-hydroxytetrahydrofuran (70.7 g, 804 mmol) in THF (2800 ml) was    added dropwise diisopropyl azodicarboxylate (195.0 g, 964 mmol) over    1.5 hours under ice-cooling. The mixture was stirred at room    temperature for 16 hours and concentrated in vacuo. The residue was    dissolved in ethanol (800 ml), and thereto was added hydrazine    monohydrate (43.4 g, 867 mmol) at room temperature, and the mixture    was heated to reflux for 4 hours and stirred at room temperature for    another 40 hours. To the reaction mixture were added ethanol    (500 ml) and a 4N hydrogen chloride solution in dioxane (300 ml,    1200 mmol). The precipitated crystals were filtered off. The    filtrate was concentrated, and the residue was recrystallized from    ethyl acetate to give the compound (25-A, monohydrochloride) (92.6    g, yield 83%) as colorless crystals.

MS (m/z) APCI: 104 [M+H]⁺

-   (2) To a solution of the compound (1-C) (3.7 g, 13.8 mmol) in    methanol (70 ml) was added sodium triacetoxyborohydride (7.33 g,    34.6 mmol) under ice-cooling. The mixture was stirred at the same    temperature for 20 minutes, then the ice bath was removed. The    reaction mixture was stirred at room temperature for another 3    hours, concentrated in vacuo, and then the residue was dissolved in    ethyl acetate, washed sequentially with water and brine, dried over    sodium sulfate and concentrated. The resulting crude ester (4.2 g)    was dissolved in a mixed solvent of methanol (40 ml) and water (10    ml), and thereto was added a 2N aqueous sodium hydroxide solution    (10.4 ml) under ice-cooling. The mixture was stirred at room    temperature for 14 hours, concentrated, acidified with 10%    hydrochloric acid and extracted with ethyl acetate. The organic    layer was washed sequentially with water and brine, dried over    sodium sulfate and concentrated. The residue was recrystallized from    ethyl acetate-hexane to give the compound (25-B) (3.30 g, yield 93%)    as colorless crystals.

MS (m/z) ESI: 255 [M−H]⁻

-   (3) A solution of the above compound (1.58 g, 6.15 mmol),    2-aminothiazole (1.23 g, 12.3 mmol) and N,N-dimethylaminopyridine    (1.13 g, 9.25 mmol) in chloroform (30 ml) was ice-cooled, and    thereto was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide    hydrochloride (1.77 g, 9.23 mmol). The reaction mixture was stirred    at room temperature for 20 hours, diluted with ethyl acetate, washed    sequentially with a 10% aqueous citric acid solution, brine, a    saturated aqueous sodium bicarbonate solution and brine, dried over    sodium sulfate and then concentrated in vacuo. The residue was    purified by silica gel chromatography (0 to 10% methanol-chloroform)    to give crude crystals. The resulting crude crystals were washed    with diethyl ether to give the compound (25-C) (1.15 g, yield 55%)    as colorless crystals.

MS (m/z) APCI: 339 [M+H]⁺

-   (4) To a solution of the above compound (957 mg, 2.83 mmol) in    dimethylsulfoxide (30 ml) were added sequentially triethylamine    (3.94 ml, 28.3 mmol) and sulfur trioxide-pyridine complex (2.25 g,    14.2 mmol) at room temperature, and the mixture was stirred at the    same temperature for 1.5 hours. To the reaction mixture was added    water, and the mixture was extracted with ethyl acetate. The organic    layer was washed sequentially with water and brine, dried over    sodium sulfate and concentrated. The residue was solidified with    diisopropyl ether to give the compound (25-D) (690 mg, yield 73%) as    a colorless solid.

MS (m/z) APCI: 337 [M+H]⁺

-   (5) To a solution of the above compound (107 mg, 0.31 mmol) and the    compound (25-A, monohydrochloride) (89 mg, 0.64 mmol) in    methanol-THF (1:1) (4 ml) was added pyridine (0.068 ml, 0.80 mmol),    and the mixture was stirred at room temperature for 16 hours and    then heated to reflux for 2 hours. To the reaction mixture was added    water, and the mixture was extracted with ethyl acetate. The organic    layer was washed sequentially with a 10% citric acid solution, water    and brine, dried over sodium sulfate and concentrated. The residue    was purified by silica gel column chromatography (0 to 10%    methanol-chloroform) to give the compound (25-E) (76 mg, (E)-isomer,    yield 32%) and the corresponding (Z)-isomer (76 mg, yield 56%) as a    colorless solid each.

MS (m/z) APCI: 422 [M+H]⁺

Example 26

To a solution of the compound of EXAMPLE 1 (958 mg, 2.13 mmol) inmethanol (40 ml) was added sodium borohydride (160 mg, 4.26 mmol) underice-cooling, and the mixture was stirred for 2 hours at the sametemperature. Acetone (1 ml) was added and the mixture was concentratedin vacuo. The resulting residue was purified by silica gel columnchromatography (3 to 10% methanol-chloroform) to give the above compound(976 mg, yield 100%) as a colorless solid.

MS (m/z) APCI: 452 [M+H]⁺

Example 27

To a solution of the compound of EXAMPLE 24-(12) (150 mg, 0.32 mmol) inmethylene chloride (3 ml) was added m-chloroperbenzoic acid (110 mg,0.48 mmol) under ice-cooling. The mixture was stirred for 2 hours at thesame temperature and concentrated in vacuo. The resulting residue waspurified by silica gel column chromatography (1 to 8%methanol-chloroform) to give the above compound (61 mg, yield 38%) as acolorless solid.

MS (m/z) APCI: 500 [M+H]⁺

Example 28

The following compounds were synthesized by treating the compounds ofEXAMPLE 24-(33) in the similar manner as EXAMPLE 2.

EXAMPLE No. No Structure MS (m/z) 28 1

563 ESI+[M + H]⁺ 28 2

549 ESI+[M + H]⁺ 28 3

522 ESI [M + H]⁺

Example 29

To a solution of the compound of EXAMPLE 1 (1.28 g, 2.85 mmol) in THF(30 ml) was added a 3M solution of methyl magnesium bromide in diethylether (2 ml, 5.98 mmol) at −78° C., and then the mixture was warmed to0° C. and stirred for 1 hour at the same temperature. To the reactionmixture was added a saturated aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed sequentially with water and brine, dried over magnesium sulfateand concentrated in vacuo. The resulting residue was purified by silicagel column chromatography (2 to 10% methanol-chloroform) to give theabove compound (1.03 g, yield 78%) as a colorless solid.

MS (m/z) APCI: 466 [M+H]⁺

Example 30

To a solution of the compound of EXAMPLE 24-(13) (100 mg, 0.224 mmol) inethanol-water (1:1) (6 ml) were added sodium carbonate (40.4 mg, 0.38mmol) and hydroxylamine hydrochloride (57.6 mg, 0.83 mmol) at roomtemperature. The reaction mixture was heated to reflux for 3 hours andextracted with chloroform, and the organic layer was washed sequentiallywith water and brine, dried over sodium sulfate and concentrated invacuo. The resulting residue was purified by silica gel columnchromatography (5 to 10% methanol-chloroform) to give the above compound(30 mg, yield 28%) as a colorless solid.

MS (m/z) APCI: 480 [M+H]⁺

Example 31

To a solution of the compound of EXAMPLE 29 (100 mg, 0.21 mmol) inmethylene chloride (7 ml) was added manganese dioxide (1 g) at roomtemperature. The mixture was stirred for 12 hours at the sametemperature and filtered through Celite. The filtrate was concentratedin vacuo, and the resulting residue was purified by silica gel columnchromatography (2 to 5% methanol-chloroform) to give the above compound(77.6 mg, yield 78%) as a colorless solid.

MS (m/z) APCI: 464 [M+H]⁺

Example 32

To a solution of the compound of EXAMPLE 24-(13) (100 mg, 0.22 mmol) inacetone-water (4:1) (5 ml) were added potassium carbonate (31 mg, 0.22mmol) and a 30% aqueous hydrogen peroxide solution (0.2 ml) underice-cooling, and the mixture was stirred at room temperature for 38hours. To the reaction mixture was added a 10% aqueous sodium sulfitesolution, and then the mixture was extracted with a mixed solvent of 10%methanol-chloroform. The organic layer was dried over sodium sulfate andconcentrated in vacuo, and the resulting residue was purified by silicagel column chromatography (10% methanol-chloroform) to give the abovecompound (74 mg, yield 71%) as a colorless solid.

MS (m/z) APCI: 465 [M+H]⁺

Example 33

The above compound was obtained as a colorless solid by reacting thecompound of EXAMPLE 31 in the similar manner as EXAMPLE 29.

MS (m/z) APCI: 480 [M+H]⁺

Example 34

To a solution of the compound of EXAMPLE 29 (100 mg, 0.21 mmol) andvinyl acetate (0.4 ml, 4.30 mmol) in ethyl acetate (5 ml) was addedLipase PS (manufactured by Amano Pharmaceutical Co., Ltd.) (1.0 g) atroom temperature, and the mixture was stirred at the same temperaturefor 3 days. The reaction mixture was filtered through Celite and thefiltrate was concentrated in vacuo. The resulting residue was purifiedby silica gel column chromatography (0 to 5% methanol-ethyl acetate) togive the above compound (36.5 mg, yield 37%) as a colorless solid.

MS (m/z) APCI: 466 [M+H]⁺

Example 35

To a solution of the compound of EXAMPLE 24-(14) (1.06 g, 2.09 mmol) inethanol (30 ml) was added a 2N aqueous sodium hydroxide solution (2.09ml, 4.18 mmol) under ice-cooling. The mixture was stirred at roomtemperature for 5 hours, acidified with 2N hydrochloric acid andextracted with methylene chloride. The organic layer was washedsequentially with water and brine, dried over magnesium sulfate andconcentrated in vacuo. The resulting residue was solidified with diethylether to give the compound (920 mg, yield 92%) as a colorless solid.

MS (m/z) ESI: 478 [M−H]⁻

Example 36

To a solution of the compound of EXAMPLE 24-(14) (100 mg, 0.20 mmol) inTHF (4 ml) was added lithium borohydride (17.2 mg, 0.79 mmol) underice-cooling, and then the mixture was stirred at room temperature for 24hours. To the reaction mixture was added methanol (4 ml) and oxalic acid(100 mg), and the mixture was stirred at room temperature for another 24hours, and thereto was added ethyl acetate. The organic layer wasseparated, washed sequentially with a saturated aqueous sodium carbonatesolution, water and brine, dried over magnesium sulfate and concentratedin vacuo. The residue was purified by silica gel column chromatography(1 to 7% methanol-chloroform) to give the above compound (27.6 mg, yield30%) as a colorless solid.

MS (m/z) APCI: 466 [M+H]⁺

Example 37

To a solution of the compound of EXAMPLE 35 (200 mg, 0.42 mmol),dimethylamine hydrochloride (102 mg, 1.25 mmol) and1-hydroxybenzotriazole (169 mg, 1.25 mmol) in methylene chloride (6 ml)was added dropwise N-ethyl-N′-(3-diethylaminopropyl)carbodiimide (0.226ml, 1.25 mmol) at room temperature. The mixture was stirred at the sametemperature for 24 hours, diluted with methylene chloride, washedsequentially with a saturated aqueous sodium carbonate solution, waterand brine, dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by NH-silica gel column chromatography (5%methanol-chloroform) to give the above compound (212 mg, yield 100%) asa colorless solid.

MS (m/z) APCI: 507 [M+H]⁺

The following compounds were synthesized by reacting the correspondingstarting compounds in the similar manner as the above-mentioned.

EXAMPLE No. No Structure MS (m/z) 37 1

493 APCI[M + H]⁺ 37 2

509 APCI[M + H]⁺

Example 38

To a solution of the compound of EXAMPLE 24-(36) (66 mg, 0.15 mmol) inethanol-THF (1:1) (6 ml) was added 10% Pd/C (60 mg). The mixture wasstirred at room temperature for 12 under hydrogen at normal pressure,filtered through Celite and then the filtrate was concentrated in vacuoto give the above compound (67 mg, yield 100%) as a colorless solid.

MS (m/z) APCI: 445 [M+H]⁺

Example 39

To a solution of the compound of EXAMPLE 24-(22) (500 mg, 1.0 mmol) inDMF (15 ml) were added tributyl(2-methyl-1-propenyl)tin (690 mg, 2.0mmol), diisopropylethylamine (0.87 ml, 5.0 mmol), lithium chloride (296mg, 7.0 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05mmol) under argon. The mixture was stirred at 120° C. for 4 hours,diluted with ethyl acetate, and thereto was added water and thenfiltered through Celite. The filtrate was washed sequentially with waterand brine, dried over sodium sulfate and concentrated in vacuo. Theresulting residue was purified by NH-silica gel column chromatography(50 to 100% chloroform-hexane) to give the above compound (268 mg, yield56%) as a colorless solid.

MS (m/z) APCI: 476 [M+H]⁺

Example 40

To a solution of the compound of EXAMPLE 39 (95 mg, 0.20 mmol) inacetone-acetonitrile-water (1:1:1) (6 ml) were added N-methylmorpholineN-oxide (59 mg, 0.50 mmol) and 10% microencapsulated osmium tetroxide(Osmium (VIII) Oxide, Microencapsulate™, Wako Pure Chemical Industries,Ltd., 102 mg, 0.04 mmol). The mixture was stirred at room temperaturefor 2 days, diluted with ethyl acetate and filtered through Celite, andthen the filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography (3-10% methanol-chloroform) to give theabove compound (96 mg, yield 94%) as a colorless solid.

MS (m/z) APCI: 510 [M+H]⁺

The following compound was synthesized by treating the correspondingstarting compound in the similar manner as the above-mentioned.

EXAMPLE No. No Structure MS (m/z) 40 1

505 APCI[M + H]⁺

Example 41

-   (1) A corresponding starting compound and the compound (1-E) were    treated in the similar manner as EXAMPLE 1-(5) to give the compound    (41-A).

MS (m/z) APCI: 519 [M+H]⁺

-   (2) The above compound (72 mg, 0.14 mmol) was dissolved in formic    acid (3 ml) at room temperature. The mixture was stirred at the same    temperature for 24 hours and concentrated. The residue was purified    by silica gel column chromatography (0 to 8% methanol-chloroform) to    give the compound (41-B) (50.7 mg, yield 87%) as a colorless solid.

MS (m/z) APCI: 419 [M+H]⁺

The following compound was synthesized by treating the correspondingstarting compound in the similar manner as the above-mentioned.

EX- AMPLE MS No. No Structure (m/z) 41 1

405APCI[M +H]⁺

Example 42

To a solution of the compound of EXAMPLE 26 (300 mg, 0.66 mmol) inmethylene chloride (10 ml) were added sequentially triethylamine (0.28ml, 1.99 mmol) and acetic anhydride (0.095 ml, 1.0 mmol) at roomtemperature. The mixture was stirred at room temperature for 16 hours,concentrated in vacuo and then to the residue was added ethylene glycol(15 ml). The mixture was heated to reflux for 8 hours, diluted withethyl acetate, and then washed sequentially with water and brine, driedover sodium sulfate and concentrated in vacuo. The resulting residue waspurified by silica gel column chromatography (0 to 5% methanol-ethylacetate) to the above compound (166 mg, yield 50%) as a colorless solid.

MS (m/z) APCI: 496 [M+H]⁺

The following compounds were synthesized by treating the correspondingstarting compounds in the similar manner as the above-mentioned.

EXAMPLE No. No Structure MS (m/z) 42 1

510 APCI[M + H]⁺ 42 2

510 APCI[M + H]⁺ 42 3

480 APCI[M + H]⁺ 42 4

494 APCI[M + H]⁺ 42 5

524 APCI[M + H]⁺

Example 43

Corresponding starting compounds were treated in the similar manner asEXAMPLE 1-(5) to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 43 1

431 APCI[M + H]⁺ 43 2

525 APCI[M + H]⁺ 43 3

535 APCI[M + H]⁺ 43 4

597 APCI[M + H]⁺ 43 5

463 APCI[M + H]⁺ 43 6

474 APCI[M + H]⁺ 43 7

550/552 ESI[M − H]⁻ 43 8

504 APCI[M + H]⁺ 43 9

474 APCI[M + H]⁺ 43 10

504 APCI[M + H]⁺ 43 11

516 APCI[M + H]⁺ 43 12

532 APCI[M + H]⁺ 43 13

554 APCI[M + H]⁺ 43 14

540 APCI[M + H]⁺ 43 15

491 APCI[M + H]⁺ 43 16

530 APCI[M + H]⁺ 43 17

571 APCI[M + H]⁺ 43 18

447 APCI[M + H]⁺ 43 19

460 APCI[M + H]⁺ 43 20

490 APCI[M + H]⁺ 43 21

450 APCI[M + H]⁺ 43 22

433 APCI[M + H]⁺ 43 23

467 APCI[M + H]⁺ 43 24

419 APCI[M + H]⁺

Example 44

-   (1) To a solution of the compound (1-E) (200 mg, 0.59 mmol) and    2-(2-aminothiazol-5-ylsulfanyl)ethanol (104 mg, 0.59 mmol) in THF    (4 ml) was added DMT-MM    (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride)    (240 mg, 0.87 mmol) at room temperature. The mixture was stirred at    the same temperature for 20 hours, diluted with ethyl acetate, and    then washed sequentially with water and brine, dried over magnesium    sulfate and concentrated in vacuo. The residue was purified by    NH-silica gel column chromatography (0 to 1% methanol-chloroform) to    give the compound (44-A) (82 mg, yield 17%) as a pale yellow solid.

MS (m/z) APCI: 819 [M+H]⁺

-   (2) To a solution of the above compound (78 mg, 0.095 mmol) in    THF-methanol-water (10:3:3) (1.6 ml) was added a 2N aqueous sodium    hydroxide solution (0.12 ml, 0.24 mmol) under ice-cooling. The    mixture was stirred at the same temperature for 2.5 hours, diluted    with ethyl acetate, and then washed sequentially with water and    brine, dried over magnesium sulfate and concentrated in vacuo. The    residue was purified by silica gel chromatography (80 to 100% ethyl    acetate-hexane) to give the compound (44-B) (31 mg, yield 66%).

MS (m/z) APCI: 498 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 44 1

512 APCI[M + H]⁺

Example 45

To a solution of the compound of EXAMPLE 44-(1) (100 mg, 0.20 mmol) andcarbon tetrabromide (321 mg, 0.97 mmol) in THF (4 ml) was addedtriphenylphosphine (256 mg, 0.97 mmol) at −10° C., and the mixture wasstirred at room temperature for 38 hours, and then concentrated invacuo. The residue was purified by NH-silica gel column chromatography(50 to 90% ethyl acetate-hexane) to give the above compound (176 mg,quantitatively).

MS (m/z) APCI: 574/576 [M+H]⁺

Example 46

To a solution of the compound of EXAMPLE 43-(14) (1800 mg, 3.34 mmol) inethanol-THF (1:3) (26 ml) was added a 2N aqueous sodium hydroxidesolution (5.0 ml, 10 mmol) under ice-cooling. The mixture was stirred atthe same temperature for 2 hours, concentrated in vacuo, and then theresidue was acidified with 2N hydrochloric acid. After diluting withethyl acetate, the mixture was washed sequentially with water and brine,dried over sodium sulfate and concentrated in vacuo. The residue wassolidified with ethyl acetate-hexane to give the above compound (1631mg, yield 96%) as colorless crystals.

MS (m/z) APCI: 510 [M−H]⁻

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 46 1

524 ESI [M − H]⁻

Example 47

The compound of EXAMPLE 43-(12) (287 mg, 0.54 mmol) was dissolved informic acid (3 ml). The mixture was stirred at room temperature for 24hours at the same temperature and concentrated in vacuo. The residue wasdissolved in chloroform, washed sequentially with a saturated aqueoussodium bicarbonate solution, water and brine, dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 5% methanol-ethyl acetate) to give the abovecompound (180 mg, yield 77%) as a colorless solid.

MS (m/z) APCI: 432 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 47 1

497 APCI[M + H]⁺ 47 2

511 APCI[M + H]⁺

Example 48

Corresponding starting compounds were treated in the similar manner asEXAMPLE 37 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 48 1

511 APCI[M + H]⁺ 48 2

525 APCI[M + H]⁺ 48 3

539 APCI[M + H]⁺ 48 4

525 APCI[M + H]⁺ 48 5

539 APCI[M + H]⁺ 48 6

553 APCI[M + H]⁺

Example 49

To a solution of the compound of EXAMPLE 24-(10) (248 mg, 0.50 mmol) inDMF (3 ml) were added tetrakis(triphenylphosphine)palladium (57 mg, 0.05mmol) and 2-mercaptoethanol (98 mg, 1.25 mmol) under argon. The mixturewas stirred at 120° C. for 3 hours, diluted with ethyl acetate, and thenwashed sequentially with water and brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (50 to 100% ethyl acetate-hexane) to give the abovecompound (72.1 mg, yield 29%) as a colorless solid.

MS (m/z) APCI: 493 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 49 1

520 APCI[M + H]⁺

Example 50

A corresponding starting compound was treated in the similar manner asEXAMPLE 1-(5) to give the above compound.

MS (m/z) APCI: 617 [M+H]⁺

Example 51

To a solution of the compound of EXAMPLE 50 (810 mg, 1.31 mmol) in THF(10 ml) was added a 1.0 M solution of tetrabutylammonium fluoride in THF(3.9 ml, 3.9 mmol) under ice-cooling. The mixture was stirred at roomtemperature for 3 hours, diluted with ethyl acetate, washed sequentiallywith water and brine, dried over sodium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatography (0to 8% methanol-chloroform) to give the above compound (646 mg, yield98%).

MS (m/z) APCI: 503 [M+H]⁺

Example 52

To a solution of the compound of EXAMPLE 26 (296 mg, 0.66 mmol) inchloroform (3 ml) were added trifluoroacetic acid (2 ml) and sodiumthiomethoxide (183 mg, 2.61 mmol). The mixture was stirred at 60° C. ina sealed tube under microwave irradiation for 3 hours, diluted withethyl acetate, washed sequentially with a saturated aqueous sodiumbicarbonate solution, water and brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (ethyl acetate) to give the above compound (281 mg, yield89%).

MS (m/z) APCI: 482 [M+H]⁺

Example 53

To a solution of the compound of EXAMPLE 52 (176 mg, 0.365 mmol) inchloroform (5 ml) was added 70% m-chloroperbenzoic acid (225 mg, 0.913mmol) under ice-cooling, and the mixture was stirred at the sametemperature for 1 hour and at room temperature for another 3 hours. Tothe reaction mixture was added a 10% sodium sulfite solution, and theorganic layer was separated, dried over sodium sulfate and concentratedin vacuo. The residue was purified by silica gel column chromatography(0 to 5% methanol-chloroform) to give the above compound (148 mg, yield79%).

MS (m/z) APCI: 514 [M+H]⁺

Example 54

To a solution of the compound of EXAMPLE 45 (50 mg, 0.087 mmol) inmethanol (1.5 ml) was added N,N-dimethyltrimethylsilylamine (459 mg,3.92 mmol) under ice-cooling. The mixture was stirred at the sametemperature for 30 minutes and at room temperature for another 18 hours,and concentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 6% methanol-chloroform) to give the above compound(41.2 mg, yield 88%).

MS (m/z) APCI: 539 [M+H]⁺

Example 55

To a solution of the compound of EXAMPLE 26 (908 mg, 2.01 mmol) and4-hydroxypiperidine (610 mg, 6.03 mmol) in toluene (60 ml) was addedp-toluenesulfonic acid monohydrate (3.65 g, 19.2 mmol) at roomtemperature, and the mixture was heated to reflux for 1 hour using aDean-Stark apparatus for azeotropic removal of the resulting water.After standing to cool, to the reaction mixture was added a saturatedaqueous sodium bicarbonate solution, and the mixture was extracted withchloroform. The organic layer was dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (aqueous ammonia-methanol-chloroform, 1:10:100) to givethe above compound (461 mg, yield 43%).

MS (m/z) APCI: 535 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 55 1

502 APCI[M + H]⁺

Example 56

To a solution of the compound of EXAMPLE 55 (107 mg, 0.2 mmol) andpyridine (0.081 ml, 1.0 mmol) in chloroform (5 ml) was added aceticanhydride (0.0284 ml, 0.3 mmol) at room temperature, and the mixture wasstirred at the same temperature for 3 hours. To the reaction mixture wasadded a saturated aqueous sodium bicarbonate solution, and the mixturewas extracted with chloroform. The organic layer was dried over sodiumsulfate, and concentrated in vacuo, and then the residue was purified bysilica gel column chromatography (0 to 10% methanol-chloroform) to givethe above compound (105 mg, yield 91%).

MS (m/z) APCI: 577 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 56 1

474 APCI[M + H]⁺

Example 57

To a mixture of the compound of EXAMPLE 55 (111 mg, 0.208 mmol) and a38% aqueous formalin solution (1 ml) in chloroform (3 ml) was addedsodium triacetoxyborohydride (132 mg, 0.603 mmol) under ice-cooling, andthe mixture was stirred at room temperature for 3 hours. To the reactionmixture was added a saturated aqueous sodium bicarbonate solution, andthe organic layer was separated, dried over magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (0 to 20% methanol-chloroform) to give the above compound(106 mg, yield 93%).

MS (m/z) APCI: 549 [M+H]⁺

Example 58

-   (1) The compound of EXAMPLE 24-(36) was treated in the similar    manner as EXAMPLE 40 to give the compound (58-A).

MS (m/z) APCI: 477 [M+H]⁺

-   (2) To a solution of the above compound (477 mg, 1.0 mmol) in    acetone (10 ml) was added an aqueous solution of sodium periodate    (235 mg, 1.10 mmol) (10 ml) under ice-cooling. The mixture was    stirred at the same temperature for 2 hours, diluted with ethyl    acetate, and then washed sequentially with a 1M aqueous sodium    sulfite solution, water and brine, dried over sodium sulfate and    concentrated in vacuo. The resulting residue was purified by silica    gel column chromatography (0 to 5% methanol-ethyl acetate) to give    the compound (58-B) (401 mg, yield 90%).

MS (m/z) APCI: 445 [M+H]⁺

Example 59

A corresponding starting compound was treated in the similar manner asEXAMPLE 29 to give the following compound.

EXAMPLE No. No Structure MS (m/z) 59

461 APCI[M + H]⁺

Example 60

A corresponding starting compound was treated in the similar manner asEXAMPLE 31 to give the following compound.

EXAMPLE No. No Structure MS (m/z) 60

459 APCI[M + H]⁺

Example 61

Corresponding starting compounds were treated in the similar manner asEXAMPLE 2 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 61 1

529 APCI[M + H]⁺ 61 2

543 APCI[M + H]⁺

Example 62

The compound (1-D), 2-methoxyethanol and the corresponding startingcompound were reacted in the similar manner as EXAMPLE 1 to give theabove compound.

MS (m/z) APCI: 428 [M+H]⁺

Corresponding starting compounds were reacted in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 62 1

553 APCI[M + H]⁺ 62 2

553 APCI[M + H]⁺ 62 3

442 ESI+[M + H]⁺ 62 4

481 APCI[M + H]⁺ 62 5

462 APCI[M + H]⁺ 62 6

450 APCI[M + H]⁺ 62 7

472 APCI[M + H]⁺ 62 8

465 APCI[M + H]⁺ 62 9

505 APCI[M + H]⁺ 62 10

464 APCI[M + H]⁺ 62 11

558 APCI[M + H]⁺ 62 12

476 APCI[M + H]⁺ 62 13

476 APCI[M + H]⁺ 62 14

476 APCI[M + H]⁺

Example 63

-   (1) To a solution of the compound (1-D) (2.5 g, 8.8 mmol) and    potassium carbonate (2.44 g, 17.7 mmol) in DMF (50 ml) was added    bromoacetonitrile (0.737 ml, 10.6 mmol) at room temperature. The    mixture was stirred at the same temperature for 15 hours, diluted    with ethyl acetate, and then washed sequentially with water and    brine, dried over sodium sulfate and concentrated in vacuo. The    resulting residue was purified by silica gel column chromatography    (40% ethyl acetate-hexane) to give the compound (63-A) (2.65 g,    yield 93%).

MS (m/z) APCI: 340 [M+H]⁺

-   (2) To a solution of the above compound (2.8 g, 8.8 mmol) in    methanol-THF (3:1) (20 ml) was added a 2N aqueous sodium hydroxide    solution (4.4 ml, 8.8 mmol) under ice-cooling, and the ice bath was    removed. The mixture was stirred at the same temperature for 30    minutes, and extracted with methylene chloride. The organic layer    was washed sequentially with water and brine, dried over magnesium    sulfate and concentrated in vacuo to give the compound (63-B) (2.8    g, quantitatively).-   (3) A corresponding starting compound was reacted with the above    compound in the similar manner as EXAMPLE 1-(5) to give the compound    (63-C).

MS (m/z) APCI: 409 [M+H]⁺

Example 64

-   (1) The compound of EXAMPLE 62-(1) (332 mg, 0.601 mmol) was    dissolved in formic acid (9 ml). The mixture was stirred at room    temperature for 24 hours and concentrated in vacuo. The residue was    dissolved in ethyl acetate and thereto was added a 4N hydrogen    chloride solution in dioxane, and the precipitated crystals were    collected to give a crude amine (308 mg) as a monohydrochloride.-   (2) To a solution of the above crude amine (60 mg) and pyridine    (0.046 ml, 0.545 mmol) in chloroform (1 ml) was added acetic    anhydride (0.015 ml, 0.163 mmol) at room temperature, and the    mixture was stirred at the same temperature for 20 hours and then    concentrated in vacuo. The resulting residue was purified by    NH-silica gel column chromatography (0 to 10% methanol-chloroform)    to give the titled compound (50.4 mg, yield 87% in 2 steps).

MS (m/z) APCI: 495 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 64 1

495 APCI[M + H]⁺

Example 65

-   (1) To a solution of the compound (1-C) (10 g, 37.2 mmol) and    cyclopentyloxyamine (8.4 g, 83.0 mmol) in methanol (100 ml) was    added pyridinium p-toluenesulfonate (10 mg, 0.04 mmol). The mixture    was stirred at room temperature for 36 hours and concentrated in    vacuo. The residue was purified by silica gel column chromatography    (25 to 33% ethyl acetate-hexane) to give (E)-ester (65-A) (3.05 g,    yield 23%) and the corresponding (Z)-ester (6.17 g, yield 47%) as a    colorless solid each.-   (2) The above compound (65-A) was reacted in the similar manner as    EXAMPLE 1-(4-2-2) to give the compound (65-B).

MS (m/z) ESI: 336 [M−H]⁻

-   (3) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (65-C).

MS (m/z) APCI: 438 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 65 1

440 APCI[M + H]⁺ 65 2

460 APCI[M + H]⁺

Example 66

-   (1) To a solution of the compound of EXAMPLE 65-(2) (4.59 g, 9.99    mmol) in methylene chloride (200 ml) was added dropwise a 1.0M    solution of boron tribromide in methylene chloride (50 ml, 50 mmol)    over 30 minutes at −78° C., and then the mixture was stirred at the    same temperature for 2 hours. To the reaction mixture was added    water, and the mixture was warmed to room temperature and then    extracted with chloroform. The organic layer was washed sequentially    with water and brine, dried over sodium sulfate and concentrated in    vacuo. The residue was solidified with a mixture of ethyl    acetate-hexane (1:1) to give the compound (66-A) (2.97 g, yield    81%).

MS (m/z) APCI: 370 [M+H]⁺

-   (2) To a solution of the above compound (500 mg, 1.35 mmol) in    THF-N,N-dimethylacetamide (1:1) (4 ml) were added potassium    tert-butoxide (379 mg, 3.38 mmol) and tert-butyl bromoacetate (0.22    ml, 1.49 mmol) under ice-cooling. The mixture was stirred at the    same temperature for 40 minutes, diluted with ethyl acetate, and    then washed sequentially with a saturated aqueous ammonium chloride    solution, water and brine, dried over sodium sulfate and    concentrated in vacuo. The residue was purified by silica gel column    chromatography (20 to 50% ethyl acetate-hexane) to give the compound    (66-B) (477 mg, yield 73%).

MS (m/z) APCI: 484 [M+H]⁺

-   (3) The above compound (448 mg, 0.927 mmol) was dissolved in formic    acid (10 ml) at room temperature. The mixture was stirred at the    same temperature for 70 hours and concentrated in vacuo, and then    the residue was solidified with diisopropyl ether to give the    carboxylic acid (66-C) (359 mg, yield 91%).

MS (m/z) ESI: 426 [M−H]⁻

-   (4) To a solution of the above compound (70 mg, 0.164 mmol) and    1-hydroxybenzotriazole (33.2 mg, 0.246 mmol) in DMF (2 ml) was added    N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg,    0.328 mmol) under ice-cooling. The mixture was stirred at the same    temperature for 1 hour. Then, thereto was added a 28% aqueous    ammonia solution (1 ml), and the mixture was stirred at the same    temperature for 30 minutes, diluted with ethyl acetate, washed    sequentially with water and brine, dried over sodium sulfate and    concentrated in vacuo. The residue was purified by silica gel column    chromatography (0 to 7% methanol-chloroform) to give the compound    (66-D) (24.7 mg, yield 35%).

MS (m/z) APCI: 427 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 66 1

441 APCI[M + H]⁺ 66 2

455 APCI[M + H]⁺

Example 67

-   (1) The compound (1-D),    (S)-1-(tert-butyldimethylsilyloxy)-2-propanol and the corresponding    starting compound were reacted in the similar manner as EXAMPLE    1-(4-1) to give the compound (67-A).

MS (m/z) APCI: 473 [M+NH₄]⁺

-   (2) The above compound was treated in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (67-B).

MS (m/z) ESI: 440 [M−H]⁻

-   (3) The above compound was treated in the similar manner as EXAMPLE    1-(5) to give the compound (67-C).

MS (m/z) APCI: 542 [M+H]⁺

-   (4) To a solution of the above compound (73.7 mg, 0.136 mmol) in THF    (3 ml) was added a 1.0M solution of tetrabutylammonium fluoride in    THF (0.54 ml, 0.54 mmol) under ice-cooling. The mixture was stirred    at room temperature for 24 hours, diluted with ethyl acetate, washed    sequentially with water and brine, dried over magnesium sulfate and    concentrated in vacuo. The residue was purified by silica gel column    chromatography (0 to 5% methanol-ethyl acetate) to give the compound    (67-D) (38 mg, yield 65%).

MS (m/z) APCI: 428 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 67 1

414 APCI[M + H]⁺ 67 2

428 APCI[M + H]⁺ 67 3

454 APCI[M + H]⁺ 67 4

454 APCI[M + H]⁺ 67 5

428 APCI[M + H]⁺ 67 6

454 APCI[M + H]⁺ 67 7

453 APCI[M + H]⁺ 67 8

468 APCI[M + H]⁺ 67 9

468 APCI[M + H]⁺

Example 68

The compound (66-A) and the corresponding starting compound were reactedin the similar manner as EXAMPLE 66-(2) to give the above compound.

MS (m/z) APCI: 464 [M+H]⁺

Example 69

-   (1) To a solution of the compound (1-D) (858 mg, 3.03 mmol) in    dimethylacetamide (5 ml) was added potassium tert-butoxide (374 mg,    3.33 mmol) under ice-cooling, and thereto was added    (7S)-iodomethyl-(2R,3R)-diphenyl-1,4-dioxaspiro[4.4]nonane    (WO2003095438) (1.40 g, 3.33 mmol). The mixture was stirred at room    temperature overnight, diluted with ethyl acetate, washed    sequentially with a 10% aqueous ammonium chloride solution, water    and brine, dried over sodium sulfate and concentrated in vacuo. The    residue was purified by silica gel column chromatography (30% ethyl    acetate-hexane) to give the compound (69-A) (856 mg, yield 49%).

MS (m/z) APCI: 593 [M+NH₄]⁺

-   (2) To a solution of the above compound (1.05 g, 1.83 mmol) in    dioxane (60 ml) was added 5N hydrochloric acid (30 ml) at room    temperature. The mixture was stirred at the same temperature for 15    hours, diluted with ethyl acetate, washed sequentially with water    and brine, dried over sodium sulfate and concentrated in vacuo. The    residue was purified by silica gel column chromatography (50% ethyl    acetate-hexane) to give the compound (69-B) (512 mg, yield 74%).

MS (m/z) APCI: 380 [M+H]⁺

-   (3) The above compound was reacted in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (69-C).

MS (m/z) ESI: 751 [2M+Na-2H]⁻

-   (4) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (69-D).

MS (m/z) APCI: 466 [M+H]⁺

Example 70

-   (1) The compound (66-A) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 66-(2) to give the compound    (70-A).

MS (m/z) APCI: 534 [M+H]⁺

-   (2) The above compound (48.5 mg, 0.091 mmol) was dissolved in a    mixed solvent of water-trifluoroacetic acid (1:3) (4 ml). The    mixture was stirred at room temperature for 4 days, concentrated in    vacuo, and then the residue was diluted with ethyl acetate, washed    sequentially with a saturated aqueous sodium bicarbonate solution,    water and brine, dried over sodium sulfate and concentrated in    vacuo. The residue was purified by gel-filtration (column: JAIGEL,    solvent: chloroform) to give the compound (70-B) (7 mg, yield 17%).

MS (m/z) APCI: 450 [M+H]⁺

Example 71

The compound (69-D) (84.3 mg, 0.181 mmol) was dissolved in a mixture ofmethanol-THF (2:1) (6 ml), and thereto was added sodium borohydride(33.8 mg, 0.89 mmol) under ice-cooling. The mixture was stirred at roomtemperature for 90 minutes, diluted with ethyl acetate, washedsequentially with water and brine, dried over sodium sulfate andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 7% methanol-chloroform) to give the above compound(79.8 mg, yield 94%).

MS (m/z) APCI: 468 [M+H]⁺

Example 72

A corresponding starting compound was treated in the similar manner asEXAMPLE 62 and EXAMPLE 64 to give the following compound.

EXAMPLE No. No Structure MS (m/z) 72

495 APCI[M + H]⁺

Example 73

To a solution of the compound of EXAMPLE 62-(7) (100 mg, 0.21 mmol) inmethanol (3 ml) was added a 4N solution of hydrogen chloride in dioxaneat room temperature, and the mixture was stirred for 3 days. To thereaction mixture was added a saturated aqueous sodium carbonatesolution, and then the mixture was extracted with chloroform. Theorganic layer was washed sequentially with water and brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified bysilica gel column chromatography (2 to 10% methanol-chloroform) to givethe above compound (54.1 mg, yield 60%).

MS (m/z) APCI: 428 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 73 1

428 APCI[M + H]⁺

Example 74

-   (1) To a solution of the compound (1-D) (1.0 g, 3.53 mmol) in THF    (40 ml) was added sodium hydride (60%, 353 mg, 8.83 mmol) under    ice-cooling, and thereto was added (R)-2-bromopropionic acid (702    mg, 4.59 mmol) and the ice bath was removed. The mixture was stirred    at room temperature for 3 hours, diluted with ethyl acetate, and    then washed sequentially with 10% hydrochloric acid, water and    brine, dried over magnesium sulfate and concentrated in vacuo. The    resulting crude carboxylic acid (74-A) was used in the next reaction    directly.-   (2) To a solution of the above crude carboxylic acid in DMF (15 ml)    were added sequentially 1-hydroxybenzotriazole (1.25 g, 9.29 mmol)    and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride    (2.97 g, 15.5 mmol) under ice-cooling, and the mixture was stirred    at the same temperature for 4 hours. Then, thereto was added an    aqueous solution of dimethylamine (50%) (5.0 ml) and the ice bath    was removed and the mixture was stirred at room temperature for 30    minutes. The reaction mixture was diluted with ethyl acetate, and    then washed sequentially with water and brine, dried over magnesium    sulfate and concentrated in vacuo. The residue was purified by    NH-silica gel column chromatography (50% ethyl acetate-hexane) to    give the compound (74-B) (594 mg, yield 44%).

MS (m/z) APCI: 383 [M+H]⁺

-   (3) The above compound was treated in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (74-C).-   (4) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (74-D).

MS (m/z) APCI: 469 [M+H]⁺

Example 75

To a solution of the compound of EXAMPLE 73 (100 mg, 0.23 mmol) andtriethylamine (0.326 ml, 2.34 mmol) in dimethylsulfoxide (3 ml) wasadded sulfur trioxide-pyridine complex (186 mg, 1.17 mmol) at roomtemperature. The mixture was stirred at the same temperature for 18hours, diluted with ethyl acetate, and then washed sequentially withwater and brine, dried over magnesium sulfate and concentrated in vacuo.The residue was purified by silica gel column chromatography (30 to 100%ethyl acetate-hexane) to give the above compound (27.9 mg, yield 28%).

MS (m/z) APCI: 426 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 75 1

466 APCI[M + H]⁺

Example 76

-   (1) To a solution of the compound (1-D) (1.0 g, 3.53 mmol) in THF    (15 ml) were added sequentially potassium tert-butoxide (396 mg,    3.53 mmol) and then β-propiolactone (382 mg, 5.30 mmol) under    ice-cooling, and the mixture was stirred at the same temperature for    2 hours and at room temperature for another 2 hours, and further at    50° C. for 2 hours. To the reaction mixture was added 10%    hydrochloric acid, and then the mixture was diluted with ethyl    acetate, washed sequentially with water and brine, dried over    magnesium sulfate and concentrated in vacuo. The resulting crude    carboxylic acid (76-A) was used in the next reaction directly.-   (2) The above crude carboxylic acid and the corresponding starting    compound were reacted in the similar manner as EXAMPLE 74-(2) to    give the compound (76-B).

MS (m/z) APCI: 383 [M+H]⁺

-   (3) The above compound was treated in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (76-C).-   (4) The above compound was reacted in the similar manner as EXAMPLE    1-(5) to give the compound (76-D).

MS (m/z) APCI: 469 [M+H]⁺

Example 77

-   (1) To a solution of the compound (77-A) (1.77 g, 3.67 mmol)    obtained from the compound (1-D) in the method of EXAMPLE 1-(4-2-1)    in THF (10 ml) was added acetic acid (0.631 ml, 11.0 mmol) under    ice-cooling, and thereto was added a 1.0M solution of    tetrabutylammonium fluoride in THF (11.0 ml, 11.0 mmol), and the    mixture was warmed to 50° C. and then stirred for 3 hours, diluted    with ethyl acetate, washed sequentially with water and brine, dried    over magnesium sulfate and concentrated in vacuo. The residue was    purified by silica gel column chromatography (50 to 80% ethyl    acetate-hexane) to give the compound (77-B) (1.21 g, yield 90%).

MS (m/z) APCI: 368 [M+H]⁺

-   (2) To a solution of the above compound (1.05 g, 2.86 mmol) in DMF    (10 ml) were added silver (I) oxide (2.99 g, 12.7 mmol) and then    methyl iodide (1.60 ml, 25.7 mmol) at room temperature, and the    mixture was stirred at 40 to 50° C. for 24 hours, diluted with ethyl    acetate, and then filtered through Celite and the filtrate was    washed sequentially with water and brine, dried over sodium sulfate    and concentrated in vacuo. The residue was purified by silica gel    column chromatography (30% ethyl acetate-hexane) to give the    compound (77-C) (617 mg, yield 57%).

MS (m/z) APCI: 382 [M+H]⁺

-   (3) The above compound was reacted in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (77-D).

MS (m/z) ESI: 366 [M−H]⁻

-   (4) The above compound was reacted in the similar manner as EXAMPLE    1-(5) to give the compound (77-E).

MS (m/z) APCI: 468 [M+H]⁺

Example 78

(3-Chloro-4-methanesulfonylphenyl)oxoacetic acid ethyl ester and thecorresponding starting compound were reacted in the similar manner asEXAMPLE 65 to give the above compound.

MS (m/z) APCI: 448/450 [M+H]⁺

Example 79

-   (1) To a solution of 5-bromo-2-cyclopropylsulfanylpyridine 6.11 g    (26.6 mmol) in diethyl ether (200 ml) was added dropwise    n-butyllithium (2.71M solution in hexane) (10.2 ml, 27.9 mmol) over    10 minutes at −78° C., and thereto was added diethyl oxalate (4.33    ml, 31.9 mmol) at the same temperature in one portion. To the    reaction mixture was added a saturated aqueous ammonium chloride    solution, and the mixture was extracted with ethyl acetate. The    organic layer was separated and then washed sequentially with water    and brine, dried over magnesium sulfate and concentrated in vacuo.    The residue was purified by silica gel column chromatography (14%    ethyl acetate-hexane) to give the above compound (79-A) (2.64 g,    yield 40%).

MS (m/z) APCI: 252 [M+H]⁺

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 65-(1) and 27 to give the    compound (79-B).

MS (m/z) APCI: 369 [M+H]⁺

(3) The above compound was reacted in the similar manner as EXAMPLE1-(4-2-2) to give the compound (79-C).

MS (m/z) ESI: 339 [M−H]⁻

-   (4) The above compound was reacted in the similar manner as EXAMPLE    1-(5) to give the compound (79-D).

MS (m/z) APCI: 441 [M+H]⁺

Example 80

-   (1) To a solution of thiophene-2-thiol (23.39 g, 200.4 mmol) in DMF    (150 ml) was added potassium tert-butoxide (24.74 g, 220 mmol) under    ice-cooling, and the mixture was stirred at the same temperature for    30 minutes and at room temperature for another 1 hour. To the above    reaction mixture was added cyclopropyl bromide (17.8 ml, 222 mmol),    and the mixture was stirred at 60° C. for 30 hours and at 80° C. for    another 5 hours. The reaction mixture was diluted with ethyl    acetate, washed sequentially with a saturated aqueous sodium    bicarbonate solution, water and brine, dried over sodium sulfate and    concentrated in vacuo. The residue was purified by NH-silica gel    chromatography (ethyl acetate) and further purified by distillation    under reduced pressure to give 2-cyclopropylsulfanylthiophene (80-A)    (18.5 g, yield 59%) as a colorless oil.

bp 70 to 100° C. (19 mmHg), MS (m/z) APCI: 157 [M+H]⁺

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(1) to give the above    compound (80-B).

MS (m/z) APCI: 257 [M+H]⁺

-   (3) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(2) to (4) to give the    above compound (80-C).

MS (m/z) ESI: 344 [M−H]⁻

-   (4) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the above    compound (80-D).

MS (m/z) APCI: 446 [M+H]⁺

Example 81

-   (1) (4-Nitrophenyl)oxoacetic acid ethyl ester and the corresponding    starting compounds were reacted in the similar manner as EXAMPLE    1-(3) to (5) to give the compound (81-A).

MS (m/z) APCI: 381 [M+H]⁺

-   (2) To a solution of the above compound (3.0 g, 7.89 mmol) in    ethanol (150 ml) was added stannous chloride dihydrate (8.9 g, 39.4    mmol) at room temperature, and the mixture was stirred at the same    temperature for 16 hours. The reaction mixture was concentrated, and    thereto was added ethyl acetate. The mixture was washed sequentially    with a saturated aqueous sodium bicarbonate solution, water and    brine, dried over magnesium sulfate and concentrated in vacuo. The    residue was purified by silica gel chromatography (5%    methanol-chloroform) to give the compound (81-B) 2.47 g, yield 89%).

MS (m/z) APCI: 351 [M+H]⁺

-   (3) To a solution of the above compound (100 mg, 0.29 mmol) and    diisopropylethylamine (0.060 ml, 0.34 mmol) in THF (5 ml) was added    p-nitrobenzoyl chloride (58 mg, 0.31 mmol) under ice-cooling, and    then the ice bath was removed and the mixture was stirred at room    temperature overnight. The reaction mixture was concentrated in    vacuo and the residue was purified by NH-silica gel chromatography    (0 to 3% methanol-chloroform) to give the compound (81-C) (160 mg,    yield 57%).

MS (m/z) APCI: 500 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 81 1

456 APCI[M + H]⁺ 81 2

475 APCI[M + H]⁺ 81 3

419 APCI[M + H]⁺ 81 4

456 APCI[M + H]⁺ 81 5

437 APCI[M + H]⁺ 81 6

455 APCI[M + H]⁺ 81 7

492 APCI[M + H]⁺ 81 8

471 APCI[M + H]⁺

Example 82

-   (1) The compound (81-B) (1.0 g, 2.9 mmol) was dissolved in a mixture    of acetic acid (5 ml) and concentrated hydrochloric acid (14 ml),    and thereto was added dropwise an aqueous solution (4 ml) of sodium    nitrite (217 mg, 3.14 mmol) under ice-cooling, and the mixture was    stirred at the same temperature for 30 minutes. To the above    reaction mixture were added sequentially copper (II) chloride    dihydrate (243 mg, 1.43 mmol) and a solution of sodium bisulfite    (4.45 g, 42.8 mmol) in 5.5M hydrochloric acid (22 ml), and the    mixture was stirred at the same temperature for 10 minutes, and then    the ice bath was removed. The mixture was stirred at room    temperature for 3 hours and poured onto ice and extracted with ethyl    acetate. The organic layer was dried over magnesium sulfate and    concentrated in vacuo to give a crude sulfonyl chloride (82-A),    which was used in the next reaction directly.-   (2) To a solution of the above compound (142 mg) in THF (2 ml) was    added a 28% aqueous ammonia solution (0.1 ml) at −5° C. The mixture    was warmed to room temperature and stirred for 1 hour, diluted with    ethyl acetate, washed sequentially with 2N hydrochloric acid, water    and brine, dried over magnesium sulfate and concentrated in vacuo.    The residue was purified by silica gel chromatography (40 to 60%    ethyl acetate-hexane) to give the compound (82-B) (54 mg, yield 46%    in 2 steps).

MS (m/z) APCI: 415 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 82 1

429 APCI[M + H]⁺ 82 2

443 APCI[M + H]⁺ 82 3

443 APCI[M + H]⁺ 82 4

457 APCI[M + H]⁺ 82 5

455 APCI[M + H]⁺ 82 6

455 APCI[M + H]⁺ 82 7

471 APCI[M + H]⁺ 82 8

485 APCI[M + H]⁺ 82 9

486 APCI[M + H]⁺ 82 10

500 APCI[M + H]⁺ 82 11

466 APCI[M + H]⁺ 82 12

457 APCI[M + H]⁺ 82 13

459 APCI[M + H]⁺ 82 14

473 APCI[M + H]⁺ 82 15

473 APCI[M + H]⁺ 82 16

487 APCI[M + H]⁺ 82 17

484 APCI[M + H]⁺ 82 18

498 APCI[M + H]⁺ 82 19

498 APCI[M + H]⁺ 82 20

526 APCI[M + H]⁺ 82 21

499 APCI[M + H]⁺ 82 22

499 APCI[M + H]⁺ 82 23

498 APCI[M + H]⁺ 82 24

512 APCI[M + H]⁺ 82 25

499 APCI[M + H]⁺ 82 26

499 APCI[M + H]⁺ 82 27

506 APCI[M + H]⁺ 82 28

520 APCI[M + H]⁺ 82 29

584 APCI[M + H]⁺ 82 30

512 APCI[M + H]⁺ 82 31

526 APCI[M + H]⁺ 82 32

555 APCI[M + H]⁺ 82 33

561 APCI[M + H]⁺ 82 34

562 APCI[M + H]⁺ 82 35

576 APCI[M + H]⁺ 82 36

590 APCI[M + H]⁺ 82 37

512 APCI[M + H]⁺ 82 38

540 APCI[M + H]⁺ 82 39

485 APCI[M + H]⁺ 82 40

485 APCI[M + H]⁺ 82 41

512 APCI[M + H]⁺ 82 42

512 APCI[M + H]⁺ 82 43

469 APCI[M + H]⁺ 82 44

487 APCI[M + H]⁺ 82 45

487 APCI[M + H]⁺ 82 46

501 APCI[M + H]⁺ 82 47

517 APCI[M + H]⁺ 82 48

533 APCI[M + H]⁺ 82 49

499 APCI[M + H]⁺ 82 50

561 APCI[M + H]⁺ 82 51

529 APCI[M + H]⁺ 82 52

560 APCI[M + H]⁺ 82 53

473 APCI[M + H]⁺ 82 54

473 APCI[M + H]⁺ 82 55

487 APCI[M + H]⁺ 82 56

487 APCI[M + H]⁺ 82 57

501 APCI[M + H]⁺ 82 58

501 APCI[M + H]⁺ 82 59

473 APCI[M + H]⁺ 82 60

473 APCI[M + H]⁺ 82 61

487 APCI[M + H]⁺ 82 62

487 APCI[M + H]⁺ 82 63

513 APCI[M + H]⁺ 82 64

526 APCI[M + H]⁺ 82 65

513 APCI[M + H]⁺ 82 66

513 APCI[M + H]⁺ 82 67

507 APCI[M + H]⁺ 82 68

509 APCI[M + H]⁺ 82 69

487 APCI[M + H]⁺ 82 70

501 APCI[M + H]⁺ 82 71

503 APCI[M + H]⁺ 82 72

531 APCI[M + H]⁺ 82 73

487 APCI[M + H]⁺ 82 74

487 APCI[M + H]⁺ 82 75

503 APCI[M + H]⁺ 82 76

499 APCI[M + H]⁺ 82 77

499 APCI[M + H]⁺ 82 78

461 APCI[M + H]⁺ 82 79

479 APCI[M + H]⁺ 82 80

489 APCI[M + H]⁺ 82 81

469 APCI[M + H]⁺ 82 82

514 APCI[M + H]⁺ 82 83

514 APCI[M + H]⁺ 82 84

528 APCI[M + H]⁺ 82 85

500 APCI[M + H]⁺ 82 86

472 APCI[M + H]⁺ 82 87

486 APCI[M + H]⁺ 82 88

500 APCI[M + H]⁺ 82 89

486 APCI[M + H]⁺ 82 90

528 APCI[M + H]⁺ 82 91

528 APCI[M + H]⁺ 82 92

542 APCI[M + H]⁺ 82 93

512 APCI[M + H]⁺ 82 94

512 APCI[M + H]⁺ 82 95

540 APCI[M + H]⁺ 82 96

512 APCI[M + H]⁺ 82 97

498 APCI[M + H]⁺ 82 98

498 APCI[M + H]⁺ 82 99

513 APCI[M + H]⁺ 82 100

526 APCI[M + H]⁺ 82 101

459 APCI[M + H]⁺ 82 102

459 APCI[M + H]⁺

Example 83

-   (1) To a solution of (4-methylthiophenyl)oxoacetic acid ethyl ester    (44.9 g, 200 mmol) in chloroform (500 ml) was added 65%    m-chloroperbenzoic acid (50 g, 188 mmol) over 30 minutes under    ice-cooling, and the mixture was stirred at the same temperature for    another 1 hour. The precipitated insoluble was filtered off, and    then to the filtrate was added a saturated aqueous sodium    bicarbonate solution, and the mixture was extracted with chloroform.    The organic layer was dried over sodium sulfate and concentrated in    vacuo. The residue was purified by silica gel chromatography (50 to    100% ethyl acetate-hexane) to give the compound (83-A) (41.1 g,    yield 85%) as a pale yellow oil.

MS (m/z) APCI: 241 [M+H]⁺

-   (2) To a solution of the above compound (41.1 g, 171 mmol) in    ethanol (400 ml) was added hydroxylamine hydrochloride (15.5 g, 222    mmol). The mixture was stirred at 50° C. for 2 hours, concentrated    in vacuo, and then the residue was dissolved in ethyl acetate,    washed sequentially with water and brine, dried over sodium sulfate    and concentrated in vacuo. To a solution of the resulting crude    oxime (45.7 g) and potassium carbonate (49.4 g, 358 mmol) in DMF    (325 ml) was added 3-(S)-tetrahydrofuranol p-toluenesulfonate (56.1    g, 232 mmol) at room temperature. The mixture was stirred for 2    days, diluted with ethyl acetate, washed sequentially with water and    brine, dried over sodium sulfate and concentrated in vacuo. The    residue was purified by silica gel chromatography (ethyl acetate) to    give the compound (83-B) (20.9 g, (E)-isomer:(Z)-isomer=72:28).

MS (m/z) APCI: 326 [M+H]⁺

-   (3) The above compound (20.35 g) was dissolved in THF-ethanol-water    (3:1:1) (350 ml), and thereto was added potassium carbonate (8.63 g,    62.5 mmol), and the mixture was stirred at room temperature for 23    hours. To the reaction mixture was added water, and the aqueous    layer was washed with ethyl acetate, acidified with concentrated    hydrochloric acid, saturated with sodium chloride and extracted with    ethyl acetate several times. The extract was dried over sodium    sulfate and concentrated in vacuo to give the compound (83-C,    (E)-isomer) (10.9 g, yield 59%) as a pale yellow oil.

MS (m/z) APCI: 298 [M+H]⁺

-   (4) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (83-D).

MS (m/z) APCI: 398 [M+H]⁺

-   (5) To a solution of the above compound (2.85 g, 7.17 mmol) in    chloroform (40 ml) was added trifluoroacetic anhydride (2.03 ml,    14.3 mmol) at room temperature, and the mixture was stirred at the    same temperature for 3 hours and concentrated in vacuo. The residue    was dissolved in methanol (15 ml), and thereto was added    triethylamine (15 ml) at room temperature. The mixture was stirred    at the same temperature for 30 minutes and concentrated in vacuo to    give the crude thiol (83-E) (2.62 g).-   (6) The above compound (150 mg, 0.41 mmol) was dissolved in DMF (2    ml), and thereto was added potassium tert-butoxide (36.6 mg, 0.33    mmol) under ice-cooling, and the mixture was stirred at the same    temperature for 10 minutes. Then, thereto was added ethyl iodide    (0.026 ml, 0.33 mmol). The mixture was stirred at the same    temperature for 2 hours and at room temperature overnight, diluted    with ethyl acetate, washed sequentially with water and brine, dried    over sodium sulfate, concentrated in vacuo. The residue was purified    by silica gel chromatography (25 to 75% ethyl acetate-hexane) to    give the compound (83-F) (96.8 mg, yield 65% in 2 steps).

MS (m/z) APCI: 396 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 83 1

426 APCI[M + H]⁺ 83 2

410 APCI[M + H]⁺ 83 3

422 APCI[M + H]⁺ 83 4

541 APCI[M + H]⁺ 83 5

499 APCI[M + NH₄]⁺ 83 6

422 APCI[M + H]⁺ 83 7

438 APCI[M + H]⁺ 83 8

438 APCI[M + H]⁺ 83 9

456 APCI[M + H]⁺ 83 10

440 APCI[M + H]⁺ 83 11

426 APCI[M + H]⁺ 83 12

440 APCI[M + H]⁺ 83 13

440 APCI[M + H]⁺ 83 14

435 APCI[M + H]⁺ 83 15

421 APCI[M + H]⁺ 83 16

454 APCI[M + H]⁺ 83 17

454 APCI[M + H]⁺

Example 84

To a solution of the compound (83-F) (88.8 mg, 0.23 mmol) in chloroform(3 ml) was added 70% m-chloroperbenzoic acid (166 mg, 0.68 mmol) at roomtemperature, and the mixture was stirred at the same temperature for 6hours and concentrated in vacuo. The residue was purified by NH-silicagel chromatography (0 to 5% methanol-chloroform) to give the abovecompound (76.8 mg, yield 80%).

MS (m/z) APCI: 428 [M+H]⁺

Corresponding starting compounds were reacted in the similar manner asEXAMPLE 83 and/or the above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 84 1

573 APCI[M + H]⁺ 84 2

514 APCI[M + H]⁺ 84 3

442 APCI[M + H]⁺ 84 4

442 APCI[M + H]⁺ 84 5

458 APCI[M + H]⁺ 84 6

454 APCI[M + H]⁺ 84 7

444 APCI[M + H]⁺ 84 8

456 APCI[M + H]⁺ 84 9

454 APCI[M + H]⁺ 84 10

470 APCI[M + H]⁺ 84 11

470 APCI[M + H]⁺ 84 12

494 APCI[M + H]⁺ 84 13

472 APCI[M + H]⁺ 84 14

458 APCI[M + H]⁺ 84 15

472 APCI[M + H]⁺ 84 16

472 APCI[M + H]⁺ 84 17

506 APCI[M + H]⁺ 84 18

467 APCI[M + H]⁺ 84 19

453 APCI[M + H]⁺ 84 20

486 APCI[M + H]⁺ 84 21

486 APCI[M + H]⁺

Example 85

-   (1) To a solution of the compound (83-E) (300 mg, 0.82 mmol) in    chloroform (10 ml) were added sequentially triethylamine (0.17 ml,    1.2 mmol) and then tri-n-butyltin chloride (0.18 ml, 0.65 mmol)    under ice-cooling. The mixture was stirred at the same temperature    for 1 hour and at room temperature for another 4 hours, diluted with    ethyl acetate, washed sequentially with water and brine, dried over    sodium sulfate and concentrated in vacuo. The residue was purified    by silica gel chromatography (10 to 60% ethyl acetate-hexane) to    give the compound (85-A) (294 mg, yield 55%).

MS (m/z) APCI: 654/656 [M+H]⁺

-   (2) To a solution of the above compound in toluene (3 ml) were added    2-bromopyridine (0.087 ml, 0.91 mmol) and    tetrakis-(triphenylphosphine)palladium (71 mg, 0.061 mmol) under    argon. The mixture was heated to reflux for 5 hours, diluted with    ethyl acetate, washed sequentially with water and brine, dried over    sodium sulfate and concentrated in vacuo. The residue was purified    by silica gel chromatography (20 to 80% ethyl acetate-hexane) to    give the compound (85-B) (76.7 mg, yield 79%).

MS (m/z) APCI: 445 [M+H]⁺

Example 86

To a solution of the compound of EXAMPLE 84-(1) (264 mg, 0.46 mmol) inethanol-THF (1:1) (12 ml) was added hydrazine hydrate (92.2 mg, 1.98mmol) at room temperature. The mixture was stirred at the sametemperature for 24 hours, and thereto was added a saturated aqueoussodium bicarbonate solution. The mixture was extracted with chloroform,and the organic layer was dried over sodium sulfate and concentrated invacuo. The residue was dissolved in ethyl acetate, and thereto was addeda 4N solution of hydrogen chloride in dioxane (0.5 ml) at roomtemperature, and the precipitated crystals were collected to give theabove compound (242 mg, quantitatively) as a hydrochloride.

MS (m/z) APCI: 443 [M+H]⁺

Example 87

-   (1) (4-Nitrophenyl)oxoacetic acid ethyl ester and the corresponding    starting compound were reacted in the similar manner as EXAMPLE    1-(3) and 1-(4-1) to give the compound (87-A).

MS (m/z) ESI: 279 [M−H]⁻

-   (2) A solution of the above compound (21.5 g, 76.7 mmol) in DMF    (358 ml) was ice-cooled and thereto were added potassium carbonate    (15.9 g, 115 mmol) and methyl iodide (5.75 ml, 92.1 mmol). The    mixture was stirred at room temperature for 4 hours, diluted with    ethyl acetate, washed sequentially with water and brine, dried over    sodium sulfate and concentrated in vacuo to give the compound (87-B)    (23.9 g, quantitatively).

MS (m/z) APCI: 295 [M+H]⁺

-   (3) The above compound was treated in the similar manner as EXAMPLE    81-(2) to give the compound (87-C).

MS (m/z) APCI: 265 [M+H]⁺

-   (4) To a solution of the above compound (3.0 g, 11.4 mmol) in a    mixture of concentrated hydrochloric acid (30 ml) and water (10 ml)    was added an aqueous solution (8 ml) of sodium nitrite (875 mg, 12.5    mmol) under ice-cooling, and the mixture was stirred at the same    temperature for 30 minutes. Then, thereto was added an aqueous    solution (12 ml) of potassium iodide (5.68 g, 34.1 mmol), and the    ice bath was removed. The mixture was stirred at room temperature    for another 1 hour, poured onto ice and extracted with ethyl    acetate. The organic layer was filtered through Celite, and then the    filtrate was washed sequentially with water and brine, dried over    magnesium sulfate and concentrated in vacuo. The residue was    purified by silica gel chromatography (30% ethyl acetate-hexane) to    give the compound (87-D) (2.57 g, yield 60%).

MS (m/z) APCI: 376 [M+H]⁺

-   (5) The above compound was reacted in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (87-E).

MS (m/z) ESI: 360 [M−H]⁻

-   (6) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (87-F).

MS (m/z) APCI: 462 [M+H]⁺

Example 88

To a suspension of the compound (87-F) (200 mg, 0.43 mmol), potassiumtert-butoxide (53.5 mg, 0.48 mmol),3-mercapto-4-methyl-4H-1,2,4-triazole (50 mg, 0.43 mmol) andbis(2-diphenylphosphinophenyl)ether (23.4 mg, 0.043 mmol) in toluene (5ml) was added tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmol)at room temperature under argon. The mixture was heated to reflux for 2hours, diluted with ethyl acetate, and then filtered through Celite andconcentrated in vacuo. The residue was purified by NH-silica gelchromatography (0 to 3% methanol-chloroform) to give the above compound(79 mg, yield 41%).

MS (m/z) APCI: 449 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EX- AM- PLE MS No. No Structure (m/z) 88 1

448APCI[M +H]⁺

Example 89

To a solution of the compound of EXAMPLE 88 (80 mg, 0.18 mmol) inmethylene chloride (3 ml) was added 65% m-chloroperbenzoic acid (189 mg,0.71 mmol) under ice-cooling, and then the ice bath was removed and themixture was stirred at room temperature for another 2 hours. To thereaction mixture was added a 10% aqueous sodium thiosulfate solution,and then the mixture was extracted with chloroform. The organic layerwas dried over magnesium sulfate and concentrated in vacuo. The residuewas purified by NH-silica gel chromatography (0 to 3%methanol-chloroform) to give the above compound (7.8 mg, yield 9%).

MS (m/z) APCI: 481 [M+H]⁺

Example 90

-   (1) To a solution of 4-hydroxyphenyloxoacetic acid ethyl ester (19.4    g, 108 mmol) in acetone (300 ml) were added sequentially potassium    carbonate (44.1 g, 319 mmol) and then allyl bromide (15.4 g, 127    mmol) under ice-cooling, and then the ice bath was removed. The    mixture was stirred at room temperature for 16 hours and heated to    reflux for another 6 hours, filtered through Celite, and then    concentrated in vacuo. The resulting residue was purified by silica    gel chromatography (17% ethyl acetate-hexane) to give the compound    (90-A) (3.38 g, yield 14%).-   (2) The above compound was reacted in the similar manner as EXAMPLE    1-(3) and 1-(4-2) to give the compound (90-B).

MS (m/z) ESI: 290 [M−H]⁻

-   (3) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (90-C).

MS (m/z) APCI: 392 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EX- AM- PLE MS No. No Structure (m/z) 90 1

394APCI[M +H]⁺ 90 2

406APCI[M +H]⁺

Example 91

-   (1) To a solution of cyclopentyloxyamine (5.0 g, 49 mmol) and    triethylamine (8.15 ml, 59 mmol) in THF (50 ml) was added dropwise a    solution of ethyl chloroglyoxylate (6.1 g, 45 mmol) in THF (25 ml)    under ice-cooling, and the mixture was stirred at the same    temperature for 30 minutes and at room temperature for another 1    hour. The insoluble was filtered off through Celite, and then the    filtrate was concentrated in vacuo, and the resulting residue was    purified by silica gel column chromatography (25% ethyl    acetate-hexane) to give the compound (91-A) (7.97 g, yield 88%) as a    pale yellow oil.

MS (m/z) APCI: 202 [M+H]⁺

-   (2) To a solution of the above compound (2.0 g, 10 mmol) in    acetonitrile (80 ml) were added sequentially triphenylphosphine    (3.93 g, 15 mmol) and carbon tetrabromide (4.97 g, 15 mmol) at room    temperature, and the mixture was heated to reflux for 3 hours. After    cooling to room temperature, the mixture was concentrated and the    residue was purified by silica gel column chromatography (3% ethyl    acetate-hexane) to give the compound (91-B) (1.87 g, yield 71%) as a    colorless oil.-   (3) To a solution of the above compound (5.28 g, 20 mmol),    4-methylthiophenylboronic acid (5.04 g, 30 mmol) in    1,2-dimethoxyethane (120 ml) were added a 1N aqueous sodium    carbonate solution (60 ml) and    dichlorobis(triphenylphosphine)palladium (1.4 g, 2.0 mmol) under    argon, and the mixture was heated at 80° C. for 30 minutes using a    microwave reactor. After cooling to room temperature, the reaction    mixture was diluted with ethyl acetate, washed sequentially with    water and brine, dried over sodium sulfate and concentrated in    vacuo. The residue was purified by silica gel column chromatography    (2 to 3% ethyl acetate-hexane) to give the compound (91-C) (4.20 g,    yield 68%) as a pale yellow oil.-   (4) To a solution of the above compound (20 g, 65 mmol) in methylene    chloride (320 ml) was added dropwise a solution of    75%-m-chloroperbenzoic acid (32.9 g, 143 mmol) in methylene chloride    (80 ml) under ice-cooling, and then the mixture was stirred at the    same temperature for 30 minutes and at room temperature for 2 hours.    The precipitate was filtered off through Celite, and then to the    filtrate was added a 10% aqueous sodium sulfite solution and the    mixture was stirred for a while. The organic layer was separated,    and then washed sequentially with a saturated aqueous sodium    carbonate solution, water and brine, dried over sodium sulfate and    concentrated in vacuo. The residue was purified by silica gel column    chromatography (25% ethyl acetate-hexane) to give the compound    (91-D) (19.35 g, yield 88%).

MS (m/z) APCI: 340 [M+H]⁺

-   (5) The above compound was reacted in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (91-E).-   (6) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (91-F).

MS (m/z) APCI: 388 [M+H]⁺

The above compounds of EXAMPLE (91-C), (91-D) or (91-E) and thecorresponding starting compounds were reacted in the similar manner as acombination of any or some of the above EXAMPLEs to give the followingcompounds.

EXAMPLE No. No Structure MS (m/z) 91 1

394 APCI[M + H]⁺ 91 2

466 APCI[M + H]⁺ 91 3

436 ESI [M − H]⁻ 91 4

419 APCI[M + H]⁺ 91 5

424 APCI[M + H]⁺ 91 6

406 APCI[M + H]⁺ 91 7

479 ESI [M − H]⁻ 91 8

435 ESI [M − H]⁻ 91 9

422 APCI[M + H]⁺ 91 10

528 APCI[M + H]⁺ 91 11

428/430 APCI[M + H]⁺ 91 12

462 APCI[M + H]⁺ 91 13

412 APCI[M + H]⁺ 91 14

466 APCI[M + H]⁺ 91 15

424 APCI[M + H]⁺ 91 16

395 APCI[M + H]⁺ 91 17

480 APCI[M + H]⁺ 91 18

506 APCI[M + H]⁺ 91 19

493 APCI[M + H]⁺ 91 20

535 APCI[M + H]⁺ 91 21

477 APCI[M + H]⁺ 91 22

495 APCI[M + H]⁺ 91 23

507 APCI[M + H]⁺ 91 24

521 APCI[M + H]⁺ 91 25

520 APCI[M + H]⁺ 91 26

550 APCI[M + H]⁺ 91 27

521 APCI[M + H]⁺ 91 28

509 APCI[M + H]⁺ 91 29

508 APCI[M + H]⁺ 91 30

507 APCI[M + H]⁺ 91 31

528 APCI[M + H]⁺ 91 32

506 ESI+[M + H]⁺ 91 33

500 ESI+[M + H]⁺ 91 34

514 ESI+[M + H]⁺ 91 35

528 ESI+[M + H]⁺ 91 36

494 ESI+[M + H]⁺ 91 37

480 ESI+[M + H]⁺ 91 38

514 APCI[M + H]⁺ 91 39

451 APCI[M + H]⁺ 91 40

465 APCI[M + H]⁺

Example 92

Corresponding starting compounds were treated in the similar manner asEXAMPLE 65 to give the following compounds.

EX- AMPLE No. No Structure MS (m/z) 92 1

380 APCI[M + H]⁺ 92 2

444/446APCI[M + H]⁺ 92 3

382 APCI[M + H]⁺

Example 93

Corresponding starting compounds were treated in the similar manner asEXAMPLE 65 to give the following compounds.

EX- AMPLE No. No Structure MS (m/z) 93 1

428/430APCI[M + H]⁺ 93 2

462/464APCI[M + H]⁺ 93 3

430/432APCI[M + H]⁺

Example 94

-   (1) The compound (1-C) was treated in the similar manner as EXAMPLE    65 to give the compound (94-A).

MS (m/z) APCI: 442 [M+H]⁺

-   (2) The above compound was reacted in the similar manner as EXAMPLE    66-(1) to give the compound (94-B).

MS (m/z) APCI: 352 [M+H]⁺

-   (3) To a solution of the above compound (95.0 mg, 0.27 mmol),    triphenylphosphine (127 mg, 0.487 mmol) and cyclopropylmethanol    (58.4 mg, 0.810 mmol) in THF (6 ml) was added dropwise diisopropyl    azodicarboxylate (0.096 ml, 0.487 mmol) under ice-cooling. The    mixture was stirred at the same temperature for 3 hours,    concentrated in vacuo, and the residue was purified by    gel-filtration (column: JAIGEL, solvent: chloroform) to give the    compound (94-C) (82.8 mg, yield 78%) as a colorless solid.

MS (m/z) APCI: 406 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asone or more combinations selected from the above methods, EXAMPLE66-(2), EXAMPLE 64 and EXAMPLE 53 to give the following compounds.

EX- AMPLE MS No. No Structure (m/z) 94 1

442APCI[M +H]⁺ 94 2

426APCI[M +H]⁺ 94 3

410APCI[M +H]⁺ 94 4

521APCI[M +H]⁺ 94 5

467APCI[M +H]⁺ 94 6

443APCI[M +H]⁺ 94 7

456APCI[M +H]⁺ 94 8

463APCI[M +H]⁺ 94 9

447APCI[M +H]⁺ 94 10

461APCI[M +H]⁺ 94 11

467APCI[M +H]⁺ 94 12

434ESI+[M +H]⁺ 94 13

472ESI+[M +H]⁺ 94 14

443ESI+[M +H]⁺ 94 15

448ESI+[M +H]⁺ 94 16

424ESI+[M +H]⁺ 94 17

408ESI+[M +H]⁺ 94 18

394ESI+[M +H]⁺ 94 19

406ESI+[M +H]⁺ 94 20

449APCI[M +H]⁺ 94 21

444ESI+[M +H]⁺ 94 22

476ESI+[M +H]⁺ 94 23

436ESI+[M +H]⁺ 94 24

436APCI[M +H]⁺ 94 25

467APCI[M +H]⁺ 94 26

460ESI+[M +H]⁺ 94 27

472ESI+[M +H]⁺ 94 28

472ESI+[M +H]⁺ 94 29

436APCI[M +H]⁺ 94 30

424APCI[M +H]⁺ 94 31

424APCI[M +H]⁺ 94 32

463APCI[M +H]⁺ 94 33

430APCI[M +H]⁺ 94 34

449APCI[M +H]⁺ 94 35

424APCI[M +H]⁺ 94 36

457APCI[M +H]⁺ 94 37

452APCI[M +H]⁺ 94 38

484APCI[M +H]⁺ 94 39

468APCI[M +H]⁺ 94 40

444APCI[M +H]⁺ 94 41

391APCI[M +H]⁺ 94 42

410ESI+[M +H]⁺ 94 43

410ESI+[M +H]⁺ 94 44

535APCI[M +H]⁺ 94 45

432APCI[M +H]⁺

Example 95

-   (1) The compound (1-D) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(4-1) to give the    compound (95-A).

MS (m/z) ESI: 362 [M−H]⁻

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (95-B).

MS (m/z) APCI: 600 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 95 1

490 APCI[M + H]⁺

Example 96

The compound (80-C) and the corresponding starting compounds werereacted in the similar manner as EXAMPLE 1-(5) to give the followingcompounds.

EXAMPLE No. No Structure MS (m/z) 96 1

442 APCI[M + H]⁺ 96 2

479 APCI[M + H]⁺

Example 97

Corresponding starting compounds were treated in the similar manner as acombination of the method of EXAMPLE 91 and the above-mentioned methodto give the following compounds.

EXAMPLE No. No Structure MS (m/z) 97 1

450 APCI[M + H]⁺ 97 2

390 APCI[M + H]⁺ 97 3

362 APCI[M + H]⁺ 97 4

387 APCI[M + H]⁺ 97 5

392 APCI[M + H]⁺ 97 6

396/398 APCI[M + H]⁺ 97 7

449 APCI[M + H]⁺ 97 8

380 APCI[M + H]⁺

Example 98

-   (1) 3-Methoxypropyl phenyl sulfide was reacted in the similar manner    as EXAMPLE 1-(1) to (3) to give the compound (98-A).

MS (m/z) APCI: 316 [M+H]⁺

-   (2) The above compound and the corresponding starting compound were    treated in the similar manner as EXAMPLE 1-(4-2-1) to give the    compound (98-B).

MS (m/z) APCI: 386 [M+H]⁺

-   (3) The above compound was treated in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (98-C).

MS (m/z) ESI: 741 [2M−H]⁻

-   (4) The above compound was treated in the similar manner as EXAMPLE    1-(5) to give the compound (98-D).

MS (m/z) APCI: 468 [M+H]⁺

The compound (98-B) was also synthesized in the following alternativemethod.

-   (1) A solution of the compound (83-C) (1.00 g, 3.36 mmol) in DMF    (15 ml) was ice-cooled, and thereto were added potassium carbonate    (697 mg, 5.04 mmol) and methyl iodide (0.0251 ml, 4.03 mmol). The    mixture was stirred at room temperature for 3 hours, diluted with    ethyl acetate, washed sequentially with water and brine, dried over    sodium sulfate and concentrated in vacuo, and then the residue was    purified by silica gel chromatography (0 to 10% methanol-ethyl    acetate) to give the compound (98-E) (1.04 g, yield 99%) as a    colorless oil.

MS (m/z) APCI: 312 [M+H]⁺

-   (2) The above compound (98-E) was reacted with the corresponding    starting compound in the similar manner as EXAMPLE 83-(5), (6) and    EXAMPLE 84 to give the compound (98-B).

MS (m/z) APCI: 386 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 98 1

498 APCI[M + H]⁺ 98 2

608 APCI[M + H]⁺ 98 3

469 APCI[M + H]⁺ 98 4

535 APCI[M + H]⁺ 98 5

505 APCI[M + H]⁺ 98 6

592 APCI[M + H]⁺ 98 7

565 APCI[M + H]⁺

Example 99

-   (1) The compound (87-C) and the corresponding starting compound were    treated in the similar manner as EXAMPLE 82 to give the compound    (99-A).

MS (m/z) APCI: 387 [M+H]⁺

-   (2) The above compound was treated in the similar manner as EXAMPLE    63-(2) to give the compound (99-B).

MS (m/z) ESI: 765 [2M-2H+Na]⁻

-   (3) The above compound was treated in the similar manner as EXAMPLE    1-(5) to give the compound (99-C).

MS (m/z) APCI: 499 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 99 1

470 APCI[M + H]⁺ 99 2

469 APCI[M + H]⁺ 99 3

609 APCI[M + H]⁺ 99 4

506 APCI[M + H]⁺ 99 5

536 APCI[M + H]⁺

Example 100

-   (1) The compound (87-C) and the corresponding starting compound were    treated in the similar manner as EXAMPLE 82 to give the compound    (100-A).

MS (m/z) APCI: 373 [M+H]⁺

-   (2) A solution of the above compound (2.89 g, 7.76 mmol) and    imidazole (1.28 g, 18.6 mmol) in DMF (48 ml) was ice-cooled, and    thereto was added tert-butyldimethylchlorosilane (1.45 g, 9.3 mmol).    The mixture was stirred at room temperature for 2 hours, diluted    with ethyl acetate, and washed with water and brine, dried over    sodium sulfate and concentrated in vacuo, and the resulting residue    was purified by silica gel chromatography (33% ethyl acetate-hexane)    to give the compound (100-B) (3.58 g, yield 95%) as a colorless oil.

MS (m/z) APCI: 487 [M+H]⁺

-   (3) The above compound was treated in the similar manner as EXAMPLE    63-(2) to give the compound (100-C).-   (4) The above compound was treated in the similar manner as EXAMPLE    1-(5) to give the compound (100-D).

MS (m/z) APCI: 569 [M+H]

-   (5) The above compound was treated in the similar manner as EXAMPLE    67-(4) to give the compound (100-E).

MS (m/z) APCI: 455 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 100 1

485 APCI[M + H]⁺ 100 2

492 APCI[M + H]⁺ 100 3

522 APCI[M + H]⁺

Example 101

-   (1) The compound (87-C) was treated in the similar manner as EXAMPLE    82-(1) and 1-(4-2-2) to give the compound (101-A).-   MS (m/z) ESI: 793 [2M-2H+Na]⁻-   (2) The above compound was reacted in the similar manner as EXAMPLE    1-(5) to give the compound (101-B).

MS (m/z) APCI: 623 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 101 1

483 APCI[M + H]⁺ 101 2

520 APCI[M + H]⁺ 101 3

550 APCI[M + H]⁺

Example 102

Corresponding starting compounds were treated in a combination of theabove-mentioned methods to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 102  1

423 APCI[M + H]⁺ 102  2

422 APCI[M + H]⁺ 102  3

576 APCI[M + H]⁺ 102  4

606 APCI[M + H]⁺ 102  5

450 APCI[M + H]⁺ 102  6

576 APCI[M + H]⁺ 102  7

532 APCI[M + H]⁺ 102  8

560 APCI[M + H]⁺ 102  9

532 APCI[M + H]⁺ 102 10

519 APCI[M + H]⁺ 102 11

567 APCI[M + H]⁺ 102 12

448 APCI[M + H]⁺ 102 13

450 APCI[M + H]⁺ 102 14

551 APCI[M + H]⁺ 102 15

441 APCI[M + H]⁺ 102 16

469 APCI[M + H]⁺ 102 17

415 APCI[M + H]⁺ 102 18

478 APCI[M + H]⁺ 102 19

538 APCI[M + H]⁺ 102 20

552 APCI[M + H]⁺ 102 21

472 APCI[M + H]⁺ 102 22

518 APCI[M + H]⁺ 102 23

508 ESI[M − H]⁻ 102 24

493/495 APCI[M + H]⁺ 102 25

569 APCI[M + H]⁺ 102 26

366 ESI[M + H]⁺

Example 103

-   (1) The compound (1-D) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(4-1) to give the    compound (103-A).-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (103-B).

MS (m/z) APCI: 536/538 [M+H]⁺

-   (3) The above compound (107 mg, 0.21 mmol) was dissolved in methanol    (2 ml), and thereto were added two drops of a 4N solution of    hydrogen chloride in dioxane. The mixture was stirred at room    temperature for 24 hours, diluted with ethyl acetate, washed with    water and brine, dried over magnesium sulfate and concentrated in    vacuo, and the resulting residue was purified by silica gel    chromatography (0 to 3% methanol-ethyl acetate) to give the compound    (103-C).

MS (m/z) APCI: 430/432 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 103 1

477 APCI[M + H]⁺ 103 2

410 APCI[M + H]⁺

Example 104

Corresponding starting compounds were treated in the similar manner asEXAMPLE 67 using the compound 67-B or the corresponding enantiomersynthesized in the method of EXAMPLE 67 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 104  1

550 ESI+[M + H]⁺ 104  2

444 ESI+[M + H]⁺ 104  3

491 ESI+[M + H]⁺ 104  4

444 ESI+[M + H]⁺ 104  5

491 ESI+[M + H]⁺ 104  6

478 APCI[M + H]⁺ 104  7

482 APCI[M + H]⁺ 104  8

461 APCI[M + H]⁺ 104  9

438/440 APCI[M + H]⁺ 104 10

418 APCI[M + H]⁺ 104 11

472 APCI[M + H]⁺ 104 12

424 APCI[M + H]⁺ 104 13

462 APCI[M + H]⁺ 104 14

454 APCI[M + H]⁺

Example 105

-   (1) To a solution of the compound (87-D) (300 mg, 0.80 mmol),    2-tributylstannylpyrazine (384 mg, 1.04 mmol) and copper (I) iodide    (15.2 mg, 0.08 mmol) in THF (6 ml) was added    tetrakis(triphenylphosphine)palladium (92.4 mg, 0.08 mmol) at room    temperature under argon, and the mixture was heated to reflux for 6    hours. After cooling, thereto was added a 10% aqueous potassium    fluoride solution and the mixture was diluted with ethyl acetate,    and then the precipitated insoluble was filtered off through Celite.    The filtrate was washed with brine, dried over magnesium sulfate and    concentrated in vacuo. The residue was purified by silica gel    chromatography (30 to 60% ethyl acetate-hexane) to give the compound    (105-A) (206 mg, yield 79%).

MS (m/z) APCI: 328 [M+H]⁺

-   (2) The above compound was reacted in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (105-B).

MS (m/z) ESI: 312 [M−H]⁻

-   (3) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (105-C).

MS (m/z) APCI: 414 [M+H]⁺

Example 106

-   (1) The compound (1-D) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(4-1) to give the    compound (106-A).

MS (m/z) ESI: 326 [M−H]⁻

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (103-B).

MS (m/z) ESI: 491 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to live the following compounds.

EXAMPLE No. No Structure MS (m/z) 106 1

444 ESI+[M + H]⁺ 106 2

424 ESI+[M + H]⁺ 106 3

454 APCI[M + H]⁺

Example 107

-   (1) The compound (1-D) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(4-1) to give the    compound (107-A).

MS (m/z) ESI: 340 [M−H]⁻

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (107-B).

MS (m/z) ESI: 458/460 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 107 1

439 ESI+[M + H]⁺ 107 2

564 ESI+[M + H]⁺ 107 3

438 ESI+[M + H]⁺ 107 4

505 APCI[M + H]⁺ 107 5

578 APCI[M + H]⁺ 107 6

468 APCI[M + H]⁺

Example 108

-   (1) The compound (1-D) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(4-2) to give the    compound (108-A).

MS (m/z) ESI: 359 [M−H]⁻

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (108-B).

MS (m/z) APCI: 524 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 108 1

477/479 APCI[M + H]⁺ 108 2

583 APCI[M + H]⁺ 108 3

457 APCI[M + H]⁺ 108 4

458 APCI[M + H]⁺ 108 5

597 APCI[M + H]⁺ 108 6

487 APCI[M + H]⁺ 108 7

461 APCI[M + H]⁺

Example 109

-   (1) The compound (1-D) and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(4-2) to give the    compound (109-A).

MS (m/z) ESI: 360 [M−H]⁻

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (109-B).

MS (m/z) APCI: 525 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 109 1

478/480 APCI[M + H]⁺ 109 2

458 APCI[M + H]⁺ 109 3

584 APCI[M + H]⁺ 109 4

459 APCI[M + H]⁺ 109 5

598 APCI[M + H]⁺ 109 6

488 APCI[M + H]⁺

Example 110

Corresponding starting compounds were reacted in the similar manner asEXAMPLE 1 using (R)-(−)-2,2-dimethyl-1,3-dioxolan-4-methanol or thecorresponding (S)-isomer to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 110 1

547 APCI[M + H]⁺ 110 2

547 APCI[M + H]⁺

Example 111

To a solution of the compound of EXAMPLE 110-(1) (300 mg, 0.55 mmol) inTHF (4 ml) was added 1N hydrochloric acid (2 ml, 2 mmol) at roomtemperature, and the mixture was stirred at the same temperature for 16hours. The mixture was extracted with chloroform, and the organic layerwas dried over sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (10% methanol-chloroform)to give the above compound (230 mg, yield 83%).

MS (m/z) APCI: 507 [M+H]⁺

The compound of EXAMPLE 110-(2) was reacted in the similar manner as theabove-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 111 1

507 APCI[M + H]⁺

Example 112

A corresponding starting compound was reacted in the similar manner asEXAMPLE 1-(5) to give the following compound.

MS (m/z) APCI: 462 [M+H]⁺

Example 113

Corresponding starting compounds were reacted in the similar manner asEXAMPLE 40 to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 113 1

475 APCI[M + H]⁺ 113 2

503 APCI[M + H]⁺

Example 114

-   (1) To a solution of 2,5-dibromopyridine (23.7 g, 100 mmol) in    diethyl ether (800 ml) was added dropwise a 2.6 M solution of    n-butyllithium in hexane (39.2 ml, 102 mmol) over 15 minutes at    −78° C. under argon, and the mixture was stirred at the same    temperature for 20 minutes. Then, thereto was added dropwise diethyl    oxalate (16.4 ml, 120 mmol) over 15 minutes. The mixture was stirred    at the same temperature for 30 minutes and warmed to 0° C. over    another 3 hours, poured into a saturated aqueous ammonium chloride    solution, and thereto was added diethyl ether. The organic layer was    separated, washed sequentially with water and brine, dried over    magnesium sulfate and concentrated in vacuo. The residue was    purified by silica gel chromatography (14% ethyl acetate-hexane) to    give the compound (114-A) (11.6 g, yield 51%).

MS (m/z) APCI: 276 [M+H+H₂O]⁺

-   (2) To a solution of the above compound (11.6 g, 44.9 mmol) in DMF    (200 ml) was added sodium thiomethoxide (3.15 g, 44.9 mmol) at room    temperature. The mixture was stirred at the same temperature    overnight, diluted with ethyl acetate, and then washed sequentially    with water and brine, dried over magnesium sulfate and concentrated    in vacuo. The residue was purified by silica gel chromatography (9%    ethyl acetate-hexane) to give the compound (114-B) (11.2 g, yield    69%).

MS (m/z) APCI: 226 [M+H]⁺

-   (3) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 65-(1) and 1-(5) to give    the compound (114-C).

MS (m/z) APCI: 363 [M+H]⁺

-   (4) In this case, the compound (114-D) which was believed to be    derived from (114-A) remaining unreacted in the reaction of the    above (3) was also obtained.

MS (m/z) APCI: 395/397 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned method and EXAMPLE 27 to synthesize the followingcompound.

EX- AMPLE No. No Structure MS (m/z) 114 1

429/431APCI[M + H]⁺

Example 115

-   (1) To a solution of 4H-[1,2,4]triazole-3-carboxylic acid methyl    ester (25.0 g, 197 mmol) in pyridine (350 ml) was added trityl    chloride (65.8 g, 236 mmol) under ice-cooling. The mixture was    stirred at room temperature 90 minutes and at 100° C. for 2 hours    and concentrated in vacuo, and then the residue was solidified with    isopropanol to give the compound (115-A) (68.8 g, yield 95%).-   (2) To a solution of the above compound (64.6 g, 175 mmol) in THF    (1000 ml) was added gradually lithium aluminum hydride (10.8 g, 284    mmol) under ice-cooling, and the ice bath was removed. After    stirring at room temperature for 3 hours, thereto was added a 10%    aqueous sodium hydroxide solution, and the suspension was filtered.    The filtrate was concentrated, and then the residue was solidified    with diethyl ether to give the compound (115-B) (34.8 g, yield 58%).

MS (m/z) ESI: 364 [M+Na]⁺

-   (3) To a solution of the above compound (17.4 g, 50.8 mmol) and    diisopropylethylamine (9.9 g, 76.2 mmol) in methylene chloride    (250 ml) was added methanesulfonyl chloride (7.76 g, 67.8 mmol)    under ice-cooling, and the mixture was stirred at the same    temperature for 30 minutes. To the reaction mixture was added water    and the organic layer was separated, and dried over sodium sulfate,    and concentrated in vacuo to give the crude methanesulfonate (115-C)    (23.6 g).-   (4) To a solution of the compound (1-D) (12.0 g, 42.4 mmol) and    potassium carbonate (17.6 g, 127 mmol) in DMF (250 ml) was added    dropwise a solution of the above sulfonate (115-C) in DMF (50 ml)    under ice-cooling, and the ice bath was removed. After stirring at    room temperature for 16 hours, the mixture was diluted with ethyl    acetate, washed sequentially with water and brine, dried over sodium    sulfate and concentrated in vacuo to give the crude ester (31.7 g,    115-D).-   (5) The above compound was reacted in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (115-E).

MS (m/z) ESI: 591 [M−H]⁻

-   (6) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (115-F).

MS (m/z) ESI: 689 [M+H]⁺

-   (7) The above compound (191 mg, 0.28 mmol) was dissolved in formic    acid (3 ml). The mixture was stirred at room temperature for 18    hours and concentrated in vacuo, and then the residue was purified    by silica gel chromatography (2 to 6% methanol-chloroform) to give    the compound (115-G) (75 g, yield 61%).

MS (m/z) APCI: 447 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 115 1

448 APCI[M + H]⁺ 115 2

587 APCI[M + H]⁺ 115 3

484 APCI[M + H]⁺ 115 4

514 APCI[M + H]⁺ 115 5

462 APCI[M + H]⁺ 115 6

477 APCI[M + H]⁺ 115 8

451 APCI[M + H]⁺

Example 116

-   (1) The compound (1-D) and tert-butyldimethylsilyl-protected    corresponding starting compound were reacted in the similar manner    as EXAMPLE 67-(1), (2) to give the compound (116-A).

MS (m/z) ESI: 466 [M−H]⁻

-   (2) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (116-B).-   (3) The above compound was reacted in the similar manner as EXAMPLE    67-(4) to give the compound (116-C).

MS (m/z) APCI: 451 [M+H]⁺

Corresponding starting compounds were treated in the similar manner asthe above-mentioned to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 116 1

487 APCI[M + H]⁺ 116 2

590 APCI[M + H]⁺ 116 3

480 APCI[M + H]⁺ 116 4

517 APCI[M + H]⁺ 116 5

574 APCI[M + H]⁺ 116 6

547 APCI[M + H]⁺

Example 117

-   (1) To a solution of 2-chloro-4-iodoaniline (25 g, 96.7 mmol) in THF    (100 ml) was added acetic anhydride (47 ml, 473 mmol) under    ice-cooling. The mixture was stirred at the same temperature for 10    minutes and at room temperature for another 18 hours, and    concentrated in vacuo. The residue was recrystallized from a mixture    of ethyl acetate-hexane (1:1) to give the compound (117-A) (28.6 g,    quantitatively).

MS (m/z) APCI: 296/298 [M+H]⁺

-   (2) To a solution of the above compound (2.4 g, 8.1 mmol) and sodium    azide (1.1 g, 16 mmol) in acetonitrile (40 ml) and methylene    chloride (5 ml) was added trifluoromethanesulfonic anhydride (3.4 g,    12 mmol) under ice-cooling, and the ice bath was removed. The    mixture was stirred at room temperature for 20 hours and    concentrated in vacuo, and then to the residue was added ethyl    acetate. The mixture was washed sequentially with water and brine,    dried over magnesium sulfate and concentrated in vacuo. The residue    was purified by silica gel chromatography (20% ethyl acetate-hexane)    to give the compound (117-B) (2.07 g, yield 80%).

MS (m/z) APCI: 321/323 [M+H]⁺

-   (3) To a solution of the above compound (4.8 g, 15 mmol),    bis(tributyltin) (17.5 g, 30 mmol) in toluene (70 ml) was added    dichlorobis(triphenylphosphine)palladium (1.06 g, 1.5 mmol) at room    temperature under argon. The mixture was stirred at 100° C. for 3    hours. After air-cooling, thereto was added a 10% aqueous potassium    fluoride solution, and the mixture was stirred at room temperature    for 1 hour, and the precipitated insoluble was filtered off through    Celite. The filtrate was dried over sodium sulfate and concentrated    in vacuo and the residue was purified by silica gel chromatography    (0 to 20% ethyl acetate-hexane) to give the compound (117-C) (4.8 g,    yield 66%).

MS (m/z) APCI: 481/483/485 [M+H]⁺

-   (4) To a solution of the above compound (7.6 g, 16 mmol),    diisopropylethylamine (3.6 ml, 20 mmol), potassium carbonate (130    mg, 0.94 mmol) and tris(dibenzylideneacetone)dipalladium (720 mg,    0.78 mmol) in THF (70 ml) was added ethyl chlorooxalate (2.64 ml, 24    mmol) at room temperature under argon, and the mixture was stirred    at the same temperature for 3 hours. To the reaction mixture was    added a 10% aqueous potassium fluoride solution, and the mixture was    stirred at the same temperature for 3 hours and diluted with diethyl    ether. The insoluble was filtered off and the organic layer of the    filtrate was separated, washed sequentially with water and brine,    dried over magnesium sulfate and concentrated in vacuo. The residue    was purified by silica gel chromatography (30% ethyl acetate-hexane)    to give the compound (117-D) (1.04 g, yield 22%).

MS (m/z) APCI: 295/297 [M+H]⁺

-   (5) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(3), 65-(1), 1-(4-2-2)    and (5) to give the compound (117-E).

MS (m/z) APCI: 432/434 [M+H]⁺

Example 118

The compound (79-C) and the corresponding starting compounds weretreated in the similar manner as EXAMPLE 1-(5) to give the followingcompounds.

EXAMPLE No. No Structure MS (m/z) 118 1

504 APCI[M + H]⁺ 118 2

563 APCI[M + H]⁺

Example 119

Corresponding starting compounds were treated in the similar manner asEXAMPLE 1-(3), (4-1), (5) to give the following compounds.

EX- AM- PLE MS No. No Structure (m/z) 119 1

498APCI[M +H]⁺ 119 2

493APCI[M +H]⁺

Example 120

A corresponding starting compound was treated in the similar manner asEXAMPLE 73 to give the following compound.

MS (m/z) APCI: 454 [M+H]⁺

Example 121

Corresponding starting compounds were treated in the similar manner asEXAMPLE 1-(4-1), (5) to give the following compounds.

EX- AM- PLE MS No. No Structure (m/z) 121 1

472APCI[M +H]⁺ 121 2

502APCI[M +H]⁺

Example 122

-   (1) To a solution of 4-bromo-3-methylbenzenesulfonyl chloride (5.4    g, 200 mmol) in THF (120 ml) was added sodium borohydride (7.6 g,    200 mmol) at room temperature, and the mixture was heated to reflux    for 16 hours. After cooling to room temperature, the reaction    mixture was diluted with ethyl acetate, washed sequentially with 5N    hydrochloric acid, water and brine, dried over sodium sulfate and    concentrated in vacuo to give the crude thiol (5.2 g,    quantitatively). A 2.0 g portion of the resulting crude thiol was    dissolved in DMSO (50 ml), and thereto was added potassium    tert-butoxide (1.2 g, 11 mmol), and the mixture was stirred at room    temperature. At the mixture became homogeneous, cyclopropyl bromide    (2.4 ml, 30 mmol) was added and the mixture was stirred at 80° C.    for 2 days. After cooling to room temperature, the reaction mixture    was poured into water and the mixture was extracted with ethyl    acetate (200 ml) twice. The organic layers were combined, washed    sequentially with water and brine, dried over sodium sulfate,    concentrated in vacuo, and then the residue was purified by silica    gel column chromatography (hexane) to give the compound (122-A) (155    mg, yield 8% in 2 steps) as an oil.-   (2) To a solution of the above compound (150 mg, 0.62 mmol) in    diethyl ether (15 ml) was added dropwise a 1.59 M solution (0.81 ml,    1.3 mmol) of tert-butyllithium in pentane at −70° C. over 4 minutes,    and thereto was added trimethyl borate (0.076 ml, 0.68 mmol) after    10 minutes in one portion, and the mixture was warmed to 0° C.    Thereto was added a saturated aqueous ammonium chloride solution,    and the mixture was stirred at room temperature for 15 minutes, and    then was extracted with ethyl acetate (20 ml). The organic layer was    dried over sodium sulfate and concentrated in vacuo to give the    crude boronic acid (122-B).-   (3) The above crude boronic acid was suspended in    1,2-dimethoxyethane (3 ml), and thereto were added the compound    (122-C) (114 mg, 0.40 mmol), which was synthesized by reacting a    corresponding starting compound in the similar manner as EXAMPLE 91,    a 1M aqueous sodium carbonate solution (1.2 ml, 1.2 mmol) and    dichlorobis(triphenylphosphine)palladium (28 mg, 0.04 mmol). After    stirring at 80° C. for 4 hours, the mixture was cooled to room    temperature, poured into water and extracted with ethyl acetate (15    ml). The organic layer was washed with brine, dried over sodium    sulfate and concentrated in vacuo. The resulting residue was    purified by silica gel column chromatography (5% to 25% hexane-ethyl    acetate) to give the compound (122-D) (30 mg, yield 20%) as an oil.

MS (m/z) APCI: 370 [M+H]⁺

-   (4) The above compound was treated in the similar manner as EXAMPLE    1-(4-2-2) to give the compound (122-E).

MS (m/z) ESI: 681 [2M−H]⁻

-   (5) The above compound and the corresponding starting compound were    reacted in the similar manner as EXAMPLE 1-(5) to give the compound    (122-F).

MS (m/z) APCI: 442 [M+H]⁺

-   (6) The above compound was treated in the similar manner as EXAMPLE    84 to give the compound (122-G).

MS (m/z) APCI: 474 [M+H]⁺

Example 123

Corresponding starting compounds were treated in a combination of themethods of EXAMPLE 1-(5), EXAMPLE 15, EXAMPLE 17 using the compound(77-D) to give the following compounds.

EXAMPLE No. No Structure MS (m/z) 123 1

494 APCI[M + H]⁺ 123 2

604 APCI[M + H]⁺ 123 3

574 APCI[M + H]⁺ 123 4

561 APCI[M + H]⁺

Example 124

To a suspension of the compound of EXAMPLE 102-(24) (80 mg, 0.162 mmol),propargyl alcohol (0.047 ml, 0.81 mmol), copper (I) iodide (6.2 mg, 0.03mmol) and triethylamine (0.5 ml, 3.6 mmol) in THF (2 ml) was addeddichlorobis(triphenylphosphine)palladium (22.7 mg, 0.03 mmol) at roomtemperature under argon, and the mixture was heated to reflux for 8hours. After cooling to room temperature, the mixture was concentratedin vacuo and the resulting residue was purified by silica gelchromatography (50 to 100% ethyl acetate-hexane) to give the abovecompound (25 mg, yield 33%).

MS (m/z) APCI: 469 [M+H]⁺

A corresponding starting compound was treated in the similar manner asthe above-mentioned to give the following compound.

EXAMPLE No. No Structure MS (m/z) 124 1

496 APCI[M + H]⁺

Example 125

A corresponding starting compound was treated in the similar manner asEXAMPLE 58 to give the above compound.

MS (m/z) APCI: 443 [M+H]⁺

Example 126

A corresponding starting compound was treated in the similar manner asEXAMPLE 29 to give the above compound.

MS (m/z) APCI: 459 [M+H]⁺

Example 127

A corresponding starting compound was treated in the similar manner asEXAMPLE 26 to give the above compound.

MS (m/z) APCI: 445 [M+H]⁺

Example 128

A corresponding starting compound was treated in the similar manner asEXAMPLE 83 and 84 to give the above compound.

MS (m/z) APCI: 498 [M+H]⁺

Example 129

-   (1) The compound of EXAMPLE 97-(4) was reacted in the similar manner    as EXAMPLE 83-(1) to give the compound (129-A).

MS (m/z) APCI: 403 [M+H]⁺

-   (2) To a solution of the above compound (100 mg, 0.25 mmol) in DMF    (2 ml) were added sequentially ammonium chloride (134 mg, 2.5 mmol)    and sodium azide (162 mg, 2.5 mmol), and the mixture was stirred at    115° C. for 3 hours. After cooling to room temperature, the mixture    was acidified with 10% hydrochloric acid, diluted with ethyl    acetate, washed sequentially with water and brine, dried over    magnesium sulfate and concentrated in vacuo to give the compound    (129-B).

MS (m/z) ESI: 444 [M−H]⁻

Example 130

To a solution of the compound of EXAMPLE (134) (100 mg, 0.22 mmol) inpyridine (5 ml) was added ethyl chlorocarbonate (0.023 ml, 0.24 mmol),and the mixture was stirred at 120° C. for 3 hours. After cooling toroom temperature, the reaction mixture was concentrated in vacuo and theresidue was purified by silica gel chromatography (0 to 5%methanol-chloroform) to give the above compound (44 mg, yield 38%).

MS (m/z) ESI: 522 [M−H]⁻

Example 131

To a solution of the compound of EXAMPLE 86 (58 mg, 0.11 mmol) anddiisopropylethylamine (0.098 ml, 0.57 mmol) in chloroform (2 ml) wasadded acetic anhydride (0.021 ml, 0.22 mmol) under ice-cooling, and themixture was stirred at room temperature overnight. To the reactionmixture was added a saturated aqueous sodium bicarbonate solution, andthe mixture was extracted with chloroform. The organic layer was washedsequentially with water and brine, dried over sodium sulfate andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (0 to 5% methanol-chloroform) to give the above compound(42 mg, yield 77%).

MS (m/z) APCI: 485 [M+H]⁺

Example 132

To a mixture of the compound of EXAMPLE 86 (59 mg, 0.11 mmol) anddiisopropylethylamine (0.060 ml, 0.0.34 mmol) in a 38% aqueous formalinsolution (1 ml) and chloroform (2 ml) was added sodiumtriacetoxyborohydride (73 mg, 0.34 mmol) under ice-cooling, and themixture was stirred at the same temperature for 1 hour and at roomtemperature for 3 hours. Then, to the reaction mixture was added asaturated aqueous sodium bicarbonate solution, and the mixture wasextracted with chloroform. The organic layer was washed sequentiallywith water and brine, dried over sodium sulfate and concentrated invacuo. The resulting residue was purified by NH-silica gelchromatography (0 to 15% methanol-ethyl acetate) to give the abovecompound (29 mg, yield 54%).

MS (m/z) APCI: 471 [M+H]⁺

Example 133

-   (1) The compound (83-E) was treated in the similar manner as EXAMPLE    83 to give the compound (133-A).-   (2) The above compound was treated in the similar manner as EXAMPLE    115-(7) to give the compound (133-B).

MS (m/z) APCI: 449 [M+H]⁺

-   (3) The compound (133-A) was treated in the similar manner as    EXAMPLE 84 to give the compound (133-C).-   (4) The above compound was treated in the similar manner as the    above (2) to give the compound (133-D).

MS (m/z) APCI: 481 [M+H]⁺

Example 134

The compound of EXAMPLE 91-(4) was treated in the similar manner asEXAMPLE 30 to give the above compound.

MS (m/z) APCI: 452 [M+H]⁺

Example 135

-   (1) The compound of EXAMPLE 125 was treated in the similar manner as    EXAMPLE 26 to give the compound (135-A).

MS (m/z) APCI: 445 [M+H]⁺

-   (2) To a solution of the compound obtained in the above (1) (78 mg,    0.18 mmol) and triphenylphosphine (92 mg, 0.35 mmol) in THF (2 ml)    was added carbon tetrabromide (116 mg, 0.35 mmol) at room    temperature, and the mixture was stirred at the same temperature for    6 hours and concentrated in vacuo. The residue was purified by    silica gel column chromatography (30 to 80% ethyl acetate-hexane) to    give the compound (135-B) (73 mg, yield 80%).

MS (m/z) APCI: 507/509 [M+H]⁺

-   (3) To a solution of the compound obtained in the above (2) (70 mg,    0.14 mmol) in methanol (3 ml) was added silver (II) oxide (34 mg,    0.28 mmol) at room temperature. The mixture was stirred at the same    temperature for 16 hours and filtered. The filtrate was concentrated    in vacuo, and the resulting residue was purified by silica gel    column chromatography (30 to 100% ethyl acetate-hexane) to give the    compound (135-C) (10 mg, yield 16%).

MS (m/z) APCI: 459 [M+H]⁺

Example 136

-   (1) A suspension of the compound (77-B) of EXAMPLE 77 (1.95 g, 5.31    mmol) and molecular sieves (4 Å, powder) (1.95 g) in    1,2-dichloroethane (38 ml) was ice-cooled and thereto were added    sequentially 1,8-bis(dimethylamino)naphthalene (3.35 g, 15.6 mmol)    and triethyloxonium tetrafluoroborate (2.97 g, 15.6 mmol). The    mixture was stirred at room temperature for 18 hours and filtered.    To the filtrate was added ethyl acetate. The mixture was washed with    brine, dried over sodium sulfate and then concentrated in vacuo, and    the residue was purified by silica gel column chromatography (33 to    50% ethyl acetate-hexane) to give the compound (136-A) (1.54 g,    yield 73%).

MS (m/z) APCI: 396 [M+H]⁺

-   (2) The compound obtained in the above (1) was treated in the    similar manner as EXAMPLE 1-(4-2-2) to give the compound (136-B).

MS (m/z) APCI: 783 [2M-2H+Na]⁻

-   (3) The compound obtained in the above (2) was treated in the    similar manner as EXAMPLE 1-(5) to give the compound (136-C).

MS (m/z) APCI: 482 [M+H]⁺

Example 137

To a solution of the compound of EXAMPLE 60 (49 mg, 0.11 mmol) andpyridine (0.50 ml) in methanol (1.0 ml) was added hydroxylaminehydrochloride (15 mg, 0.21 mmol), and the mixture was stirred at roomtemperature for 16 hours. To the reaction mixture was added chloroform,and the mixture was washed with water and brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel column chromatography (0 to 5% methanol-chloroform) to give thetitled compound (52 mg, quantitatively).

MS (m/z) APCI: 474 [M+H]⁺

Example 138

-   (1) The compound (1-E) of EXAMPLE 1 was treated in the similar    manner as EXAMPLE 1-(5) to give the compound (138-A).

MS (m/z) APCI: 637 [M+H]⁺

-   (2) A solution of the compound obtained in the above (1) (3.20 g,    5.03 mmol) in chloroform-trifluoroacetic acid (1:1) (80 ml) was    stirred at room temperature for 2 days. The reaction mixture was    concentrated in vacuo and the residue was chased with toluene, and    then to the residue was added a saturated aqueous sodium bicarbonate    solution. The mixture was extracted with chloroform. The extract was    dried over sodium sulfate and concentrated in vacuo. The residue was    then purified by silica gel column chromatography    (methanol-chloroform-ammonia water 200:10:1 to 100:10:1) to give the    compound (138-B) (2.06 g, yield 77%).

MS (m/z) APCI: 537 [M+H]⁺

Example 139

Corresponding starting compounds were treated in the similar manner asany of the above EXAMPLEs to give the following compounds.

EXAMPLE No. No. Structure MS (m/z) 139 1

582 APCI[M + H]⁺ 139 2

568 APCI[M + H]⁺ 139 3

430 APCI[M + H]⁺ 139 4

457 APCI[M + H]⁺ 139 5

462 ESI [M −H]⁻ 139 6

522 ESI [M −H]⁻ 139 7

456 ESI [M −H]⁻ 139 8

494 ESI [M −H]⁻ 139 9

504 ESI [M −H]⁻ 139 10

540/542 ESI[M − H]− 139 11

476 ESI [M −H]− 139 12

476 ESI [M −H]− 139 13

ESI 512 [M −H]− 139 14

530 ESI [M −H]− 139 15

506 APCI[M + H]+ 139 16

506 APCI[M + H]+ 139 17

556/558APCI [M + H]+ 139 18

506 APCI[M + H]+ 139 19

534 APCI[M + H]+ 139 20

542 APCI[M + H]+ 139 21

492 APCI[M + H]+ 139 22

524 APCI[M + H]+ 139 23

459 APCI[M + H]+ 139 24

502 ESI [M −H]− 139 25

561 APCI[M + H]+ 139 26

601 APCI[M + H]+ 139 27

605 APCI[M + H]+ 139 28

611 APCI[M + H]+ 139 29

575 APCI[M + H]+ 139 30

475 APCI[M + H]+ 139 31

558 APCI[M + H]+ 139 32

572 APCI[M + H]+ 139 33

482 APCI[M + H]+ 139 34

508 APCI[M + H]+ 139 35

618 APCI[M + H]+ 139 36

575 APCI[M + H]+ 139 37

588 APCI[M + H]+ 139 38

559 APCI[M + H]+ 139 39

546 APCI[M + H]+ 139 40

485 APCI[M + H]+ 139 41

475 APCI[M + H]+ 139 42

460 APCI[M + H]+ 139 43

489 APCI[M + H]+ 139 44

474 APCI[M + H]+ 139 45

516 APCI[M + H]+ 139 46

528 APCI[M + H]+ 139 47

602 APCI[M + H]+ 139 48

588 APCI[M + H]+ 139 49

450 APCI[M + H]+ 139 50

570 APCI[M + H]+ 139 51

498 APCI[M + H]+ 139 52

588 APCI[M + H]+ 139 53

588 APCI[M + H]+ 139 54

573 APCI[M + H]+ 139 55

474 APCI[M + H]+ 139 56

436 APCI[M + H]+ 139 57

478 APCI[M + H]+ 139 58

586 APCI[M + H]+ 139 59

544 APCI[M + H]+ 139 60

558 APCI[M + H]+ 139 61

574 APCI[M + H]+ 139 62

572 APCI[M + H]+ 139 63

560 APCI[M + H]+ 139 64

560 APCI[M + H]+ 139 65

558 APCI[M + H]+ 139 66

588 APCI[M + H]+ 139 67

574 APCI[M + H]+ 139 68

572 APCI[M + H]+ 139 69

558 APCI[M + H]+ 139 70

572 APCI[M + H]+ 139 71

559 APCI[M + H]+ 139 72

502 APCI[M + H]+ 139 73

532 APCI[M + H]+ 139 74

546 APCI[M + H]+ 139 75

559 APCI[M + H]+ 139 76

APCI 537[M + H]+ 139 77

APCI 551[M + H]+ 139 78

APCI 579[M + H]+ 139 79

545 [M + H]+ 139 80

532 [M + H]+ 139 81

588 [M + H]+ 139 82

483 APCI[M + H]+ 139 83

484 APCI[M + H]+ 139 84

484 APCI[M + H]+ 139 85

513 APCI[M + H]+ 139 86

623 APCI[M + H]+ 139 87

550 APCI[M + H]+ 139 88

464 APCI[M + H]+ 139 89

514 APCI[M + H]+ 139 90

494 APCI[M + H]+ 139 91

508 APCI[M + H]+ 139 92

503 APCI[M + H]+ 139 93

522 APCI[M + H]+ 139 94

504 APCI[M + H]+ 139 95

609 APCI[M + H]+ 139 96

469 APCI[M + H]+ 139 97

506 APCI[M + H]+ 139 98

536APCI [M + H]+ 139 99

579 APCI[M + H]+ 139 100

567 APCI[M + H]+ 139 101

470 APCI[M + H]+ 139 102

499 APCI[M + H]+ 139 103

490 APCI[M + H]+ 139 104

480 APCI[M + H]+ 139 105

593 ESI[M + H]+ 139 106

501 APCI[M + H]+ 139 107

497 APCI[M + H]+ 139 108

527 APCI[M + H]+ 139 109

498 APCI[M + H]+ 139 110

564 APCI[M + H]+ 139 111

508 APCI[M + H]+ 139 112

518 APCI[M + H]+ 139 113

567 APCI[M + H]+ 139 114

579 APCI[M + H]+ 139 115

480 APCI[M + H]+ 139 116

496 APCI[M + H]+ 139 117

512 APCI[M + H]+ 139 118

541 APCI[M + H]+ 139 119

651 APCI[M + H]+ 139 120

515 APCI[M + H]+ 139 121

511 APCI[M + H]+ 139 122

609 APCI[M + H]+ 139 123

532 APCI[M + H]+ 139 124

479 APCI[M + H]+ 139 125

581 APCI[M + H]+ 139 126

593 APCI[M + H]+ 139 127

484 APCI[M + H]+ 139 128

513 APCI[M + H]+ 139 129

494 APCI[M + H]+ 139 130

510 APCI[M + H]+ 139 131

491 APCI[M + H]+ 139 132

495 APCI[M + H]+ 139 133

490 APCI[M + H]+ 139 134

557 APCI[M + H]+ 139 135

520 APCI[M + H]+ 139 136

614 APCI[M + H]+ 139 137

630 APCI[M + H]+ 139 138

588 APCI[M + H]+ 139 139

501 APCI[M + H]+ 139 140

600 APCI[M + H]+ 139 141

470 APCI[M + H]+ 139 142

467 APCI[M + H]+ 139 143

496 APCI[M + H]+ 139 144

576 APCI[M + H]+ 139 145

563 APCI[M + H]+ 139 146

604 APCI[M + H]+ 139 147

590 APCI[M + H]+ 139 148

564 APCI[M + H]+ 139 149

603 APCI[M + H]+ 139 150

589 APCI[M + H]+ 139 151

532 APCI[M + H]+ 139 152

518 APCI[M + H]+ 139 153

562 APCI[M + H]+ 139 154

576 APCI[M + H]+ 139 155

589 APCI[M + H]+ 139 156

507 APCI[M + H]+ 139 157

518 APCI[M + H]+ 139 158

530 APCI[M + H]+ 139 159

489 APCI[M + H]+ 139 160

462 APCI[M + H]+ 139 161

491 APCI[M + H]+ 139 162

505 APCI[M + H]+ 139 163

521 APCI[M + H]+ 139 164

486 APCI[M + H]+ 139 166

493 APCI[M + H]+ 139 167

487 APCI[M + H]+ 139 168

590 APCI[M + H]+ 139 169

588 APCI[M + H]+ 139 170

602 APCI[M + H]+ 139 171

476 APCI[M + H]+ 139 172

608 APCI[M + H]+ 139 173

521 APCI[M + H]+ 139 174

506 APCI[M + H]+ 139 175

514 APCI[M + H]+ 139 176

511 APCI[M + H]+ 139 177

540 APCI[M + H]+ 139 178

607 APCI[M + H]+ 139 179

622 APCI[M + H]+ 139 180

580 APCI[M + H]+ 139 181

493 APCI[M + H]+ 139 182

482 APCI[M + H]+ 139 183

512 APCI[M + H]+ 139 184

578 APCI[M + H]+ 139 185

486 APCI[M + H]+ 139 186

483 APCI[M + H]+ 139 187

579 APCI[M + H]+ 139 188

592 APCI[M + H]+ 139 189

606 APCI[M + H]+ 139 190

519 APCI[M + H]+ 139 191

549 APCI[M + H]+ 139 192

618 APCI[M + H]+ 139 193

500 APCI[M + H]+ 139 194

496 APCI[M + H]+ 139 195

497 APCI[M + H]+ 139 196

526 APCI[M + H]+ 139 197

563 APCI[M + H]+ 139 199

593 APCI[M + H]+ 139 200

636 APCI[M + H]+ 139 201

594 APCI[M + H]+ 139 202

492 APCI[M + H]+ 139 203

507 APCI[M + H]+ 139 204

523 APCI[M + H]+ 139 205

517 APCI[M + H]+ 139 206

618 APCI[M + H]+ 139 207

632 APCI[M + H]+ 139 208

578 APCI[M + H]+ 139 209

566 APCI[M + H]+ 139 210

479 APCI[M + H]+ 139 211

464 APCI[M + H]+ 139 212

495 APCI[M + H]+ 139 213

577 APCI[M + H]+ 139 214

564 APCI[M + H]+ 139 215

536 APCI[M + H]+ 139 216

606 APCI[M + H]+ 139 217

592 APCI[M + H]+ 139 218

605 APCI[M + H]+ 139 219

591 APCI[M + H]+ 139 220

578 APCI[M + H]+ 139 221

534 APCI[M + H]+ 139 222

520 APCI[M + H]+ 139 223

564 APCI[M + H]+ 139 224

578 APCI[M + H]+ 139 225

591 APCI[M + H]+ 139 226

477 APCI[M + H]+ 139 227

592 APCI[M + H]+ 139 228

590 APCI[M + H]+ 139 229

604 APCI[M + H]+ 139 230

483 APCI[M + H]+ 139 231

479 APCI[M + H]+ 139 232

480 APCI[M + H]+ 139 233

509 APCI[M + H]+ 139 234

546 APCI[M + H]+ 139 235

577 APCI[M + H]+ 139 236

564 APCI[M + H]+ 139 237

606 APCI[M + H]+ 139 238

533 APCI[M + H]+ 139 239

563 APCI[M + H]+ 139 240

496 APCI[M + H]+ 139 241

462 APCI[M + H]+ 139 242

590 APCI[M + H]+ 139 243

595 APCI[M + H]+ 139 244

565 APCI[M + H]+ 139 245

553 APCI[M + H]+ 139 246

480 APCI[M + H]+

Example 140

Corresponding starting compounds are treated in the similar manner asany of the above EXAMPLEs to give the following compounds.

EXAMPLE No. No. Structure 140 1

140 2

140 3

140 4

140 5

140 6

140 7

140 8

140 9

140 10

140 11

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140 114

140 115

140 116

140 117

140 118

140 119

140 120

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140 125

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140 128

140 129

140 130

140 131

140 132

140 133

140 134

140 135

140 136

140 137

140 138

140 139

140 140

140 141

140 142

140 143

140 144

140 145

140 146

140 147

140 148

140 149

140 150

140 151

140 152

140 153

140 154

140 155

140 156

140 157

140 158

140 159

140 160

140 161

140 162

140 163

140 164

140 165

140 166

140 167

140 168

140 169

140 170

140 171

140 172

140 173

140 174

140 175

140 176

140 177

140 178

140 179

140 180

140 181

140 182

140 183

140 184

140 185

140 186

140 187

140 188

140 189

140 190

140 191

140 192

140 193

140 194

140 195

140 196

140 197

140 198

140 199

140 200

140 201

140 202

140 203

140 204

140 205

140 206

140 207

140 208

140 209

140 210

140 211

140 212

140 213

140 214

140 215

140 216

140 217

140 218

140 219

140 220

140 221

140 222

140 223

140 224

140 225

140 226

140 227

140 228

140 229

140 230

140 231

140 232

140 233

140 234

140 235

140 236

140 237

140 238

140 239

140 240

140 241

140 242

140 243

140 244

140 245

140 246

140 247

140 248

140 249

140 250

140 251

140 252

140 253

140 254

140 255

140 256

140 257

140 258

140 259

140 260

140 261

140 262

140 263

140 264

140 265

140 266

140 267

140 268

140 269

140 270

140 271

140 272

140 273

140 274

140 275

140 276

140 277

140 278

140 279

140 280

140 281

140 282

140 283

140 284

140 285

140 286

140 287

140 288

140 289

140 290

140 291

140 292

140 293

140 294

140 295

140 296

140 297

140 298

140 299

140 300

140 301

140 302

140 303

140 304

140 305

140 306

140 307

140 308

140 309

140 310

140 311

140 312

140 313

140 314

140 315

140 316

140 317

140 318

140 319

140 320

140 321

140 322

140 323

140 324

140 325

140 326

140 327

140 328

140 329

140 330

140 331

140 332

140 333

140 334

140 335

140 336

140 337

140 338

140 339

140 340

140 341

140 342

140 343

140 344

140 345

140 346

140 347

140 348

140 349

140 350

140 351

140 352

140 353

140 354

140 355

140 356

140 357

140 358

140 359

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140 361

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140 364

140 365

140 366

140 367

140 368

140 369

140 370

140 371

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140 469

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140 494

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140 496

140 497

140 498

Reference Example 1

To a solution of 2-tert-butyloxycarbonylaminothiazole (88.0 g, 439 mmol)in THF (1760 ml) was added dropwise a 1.59M solution of n-butyllithiumin hexane (729 ml, 1159 mmol) over 20 minutes at −78° C., and themixture was warmed to −10° C. over 1 hour. The mixture was cooled againto −78° C. and thereto was added DMF (102 ml, 0.132 mmol) in oneportion. The acetone-dry ice bath was removed. The mixture was stirredfor 30 minutes, and then poured into cold water (1000 ml) and theretowas added ethyl acetate (2000 ml). The organic layer was washedsequentially with water and brine, dried over anhydrous magnesiumsulfate and the solvents were removed. The residue was recrystallizedfrom ethyl acetate to give2-tert-butyloxycarbonylaminothiazole-5-carbaldehyde (74.8 g).

mp. 173 to 175° C.

MS (m/z) APCI: 229 (M+H)⁺

To a solution of the above2-tert-butyloxycarbonylaminothiazole-5-carbaldehyde (64.5 g, 282 mmol)in methylene chloride (322 ml) was added dropwise trifluoroacetic acid(322 ml) under ice-cooling over 20 minutes. The mixture was stirred atroom temperature for 2 hours and the solvent was removed by evaporation.Thereto was added chloroform (50 ml), and then added a 4N hydrogenchloride solution in dioxane (300 ml) dropwise under ice-cooling. Afterremoving the solvents, the residue was washed with ethyl acetate andcollected to give the titled compound (41.3 g) as monohydrochloridethereof.

mp. 190 to 194° C. (decomposed)

MS (m/z) APCI: not detected

Reference Example 2

To a solution of 2-tert-butyloxycarbonylaminothiazole (60.0 g, 299 mmol)in THF (1200 ml) was added dropwise a 1.59M solution of n-butyllithiumin hexane (428 ml, 659 mmol) at −78° C. over 20 minutes, and the mixturewas warmed to −10° C. over 1 hour and cooled again to −78° C. Theretowas added N-fluorobenzenesulfonylimide (142 g, 449 mmol) in one portion.The acetone-dry ice bath was removed and the mixture was stirred for 30minutes poured into cold water (1000 ml). Thereto was added ethylacetate (1200 ml) and the organic layer was washed sequentially with 2Nhydrochloric acid, water and brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (15% ethyl acetate-hexane=3:1), and then recrystallizedfrom diethyl ether to give 2-tert-butyloxycarbonylamino-5-fluorothiazole(45.1 g).

mp. 157 to 159° C.

MS (m/z) APCI: 219 (M+H)⁺

To a solution of the above 2-tert-butyloxycarbonylamino-5-fluorothiazole(38.0 g, 174 mmol) in methylene chloride (190 ml) was added dropwisetrifluoroacetic acid (190 ml) over 20 minutes under ice-cooling. Themixture was stirred at room temperature for 2.5 hours, and concentrated.Thereto was added chloroform (20 ml) and 4N hydrogen chloride solutionin dioxane (180 ml) dropwise under ice-cooling. After concentration, theresidue was washed with ethyl acetate and collected to give the titledcompound (24.6 g) as monohydrochloride thereof.

mp. 142 to 144° C. (decomposed)

MS (m/z) APCI: 119 (M+H)⁺

Reference Example 3

-   (1) To an aqueous solution (400 ml) of a compound of REFERENCE    EXAMPLE 1 (80.0 g, 486 mmol) was added dropwise a 28% ammonia water    (40 ml) at room temperature, and then the precipitated crystals were    collected and dried to give the free aldehyde.-   (2) The above product was suspended in methanol (600 ml) and thereto    was added sodium borohydride (27.6 g, 729 mmol) under ice-cooling,    and the mixture was stirred at room temperature for 1 hour. To the    reaction solution were added acetone (30 ml) and water (50 ml), and    then the mixture was concentrated in vacuo. The resulting residue    was purified by silica gel column chromatography (20 to 25%    methanol-chloroform) to give 2-amino-5-hydroxymethylthiazole (45.2    g, yield 71%).

MS (m/z) APCI: 131 (M+H)⁺

-   (3) The above product (45.2 g) was dissolved in a 2M solution of    hydrogen chloride in methanol and the mixture was stirred at 60° C.    for 5 hours. The reaction mixture was concentrated and then the    residue was solidified with a mixture of methanol and diethyl ether    to give the titled compound (49.8 g, yield 79%) as monohydrochloride    thereof.

MS (m/z) APCI: 145 (M+H)⁺

Reference Example 4

5-Methoxy[1,3]thiazolo[5,4-b]pyridin-2-amine (5.0 g, 27.6 mmol) wasdissolved in 30% hydrogen bromide in acetic acid (50 ml). The mixturewas stirred at 130° C. for 3 hours and cooled to room temperature, andthen the solvents were removed in vacuo and the residue was solidifiedwith diethyl ether to give 2-amino[1,3]thiazolo[5,4-b]pyridin-5-oldihydrobromide (9.11 g, quantitatively) as colorless crystals.

MS (m/z) APCI: 168 (M+H)⁺

Reference Example 5

A solution of a compound of REFERENCE EXAMPLE 4 (1.18 g, 3.59 mmol),dimethylaminoethyl chloride monohydrochloride (569 mg, 3.95 mmol) andcesium carbonate (6.43 g, 19.75 mmol) in DMF (30 ml) was stirred at 60°C. for 2 hours. After cooling to room temperature, thereto was addedacetic acid (2.26 ml, 39.5 mmol) and the mixture was diluted with waterto a homogeneous solution and then concentrated in vacuo. The residuewas purified by silica gel column chromatography (NH-silica gel; 50%ethyl acetate-hexane) to give the titled compound (273 mg, yield 32%) aspale yellow crystals.

MS (m/z) APCI: 239 (M+H)⁺

Reference Example 6

A solution of a compound of REFERENCE EXAMPLE 4 (1.54 g, 4.68 mmol),ethyl bromoacetate (0.571 ml, 5.15 mmol) and cesium carbonate (6.86 g,21.06 mmol) in DMF (40 ml) was stirred at room temperature for 30minutes. Thereto was added acetic acid (2.47 ml, 43.2 mmol) and themixture was diluted with water to a homogeneous solution and thesolvents were removed in vacuo. The residue was purified by silica gelcolumn chromatography (NH-silica gel; ethyl acetate) and solidified withdiisopropyl ether to give the titled compound (862 mg, yield 67%) ascolorless crystals.

MS (m/z) APCI: 254 (M+H)⁺

Reference Example 7

A corresponding starting compound was treated in the similar manner asREFERENCE EXAMPLE 5 to give the titled compound.

MS (m/z) APCI: 282 (M+H)⁺

Reference Example 8

To a solution of a compound of REFERENCE EXAMPLE 6 (862 mg, 3.40 mmol)in THF (20 ml) was added lithium borohydride (222 mg, 10.21 mmol) atroom temperature, and the mixture was stirred for 24 hours. To thereaction mixture was added 10% hydrochloric acid for degradation of theexcess reagents. Thereto was added a saturated aqueous sodiumbicarbonate solution, and the mixture was extracted with 20%methanol-chloroform. The organic layer was separated and the solventswere removed. The resulting residue was purified by silica gel columnchromatography (5 to 20% methanol-chloroform) to give the titledcompound (369 mg, yield 51%) as colorless crystals.

MS (m/z) APCI: 212 (M+H)⁺

The above compound was also synthesized by the following alternativemethod.

-   (1) To a solution of the compound (8-a) (5.18 g, 32.7 mmol) and    ethylene glycol (20.28 g, 327 mmol) in DMF (20 ml) was added    potassium carbonate (13.55 g, 98.0 mmol). The mixture was stirred at    room temperature for 2 hours, diluted with ethyl acetate, washed    with water and brine, dried over sodium sulfate and concentrated in    vacuo. The residue was recrystallized from ethyl acetate-hexane to    give the compound (8-b) (5.59 g, yield 93%) as yellow crystals.

MS (APCI): 185 (M+H)⁺

-   (2) To a solution of the compound (8-b) (5.57 g, 30.25 mmol) in    ethanol (50 ml) was added 10% Pd—C (0.50 g). The mixture was stirred    vigorously for 2 hours under hydrogen and concentrated in vacuo to    give the crude amine.-   (3) To a solution of the above amine in acetic acid (100 ml) was    added potassium thiocyanate (17.64 g, 182 mmol), and thereto was    added dropwise bromine (1.62 ml, 31.8 mmol) under cooling with ice    bath. The mixture was stirred at room temperature overnight, then    concentrated in vacuo. The residue was chased with toluene, purified    by silica gel chromatography (NH-silica gel;    methanol-chloroform=20:1 to 10:1) and triturated with ethyl acetate    to give the compound (8-c) (5.55 g, yield 87%) as colorless    crystals.

MS (APCI): 212 (M+H)⁺

Reference Example 9

The compound of REFERENCE EXAMPLE 4 was treated with 2-bromoacetamide inthe similar manner as REFERENCE EXAMPLE 5 to give the titled compound.

MS (m/z) APCI: 225 (M+H)⁺

Reference Example 10

The compound of REFERENCE EXAMPLE 4 was treated with2-bromo-N-methylacetamide in the similar manner as REFERENCE EXAMPLE 5to give the titled compound.

MS (m/z) APCI: 239 (M+H)⁺

Reference Example 11

-   (1) To a solution of the compound of REFERENCE EXAMPLE 9 (1380 mg,    3.02 mmol) in THF (40 ml) was added lithium aluminum hydride (1.17    g, 30.8 mmol) at room temperature, and the mixture was stirred at    room temperature for 20 hours. After degrading excess reagents with    a 30% aqueous ammonia solution, the mixture was filtered and the    filtrate was concentrated in vacuo. The resulting residue was    purified by silica gel column chromatography (30% aqueous    ammonia-methanol-chloroform=0.1:1:5) to give an amine (150 mg).-   (2) To a suspension of the compound obtained in the above (1) (150    mg, 0.713 mmol) in THF (10 ml) was added a solution of    di-tert-butyldicarbonate (187 mg, 0.856 mmol) in THF (5 ml) at room    temperature, and the mixture was stirred at room temperature for 90    minutes. To the reaction mixture was added a 30% aqueous ammonia    solution, and the mixture was stirred at room temperature for 30    minutes, and then diluted with ethyl acetate, washed with brine,    dried over sodium sulfate and concentrated in vacuo. The resulting    residue was purified by silica gel column chromatography (0 to 5%    methanol-chloroform) to give the titled compound (177 mg, yield 9%    in 2 steps) as colorless solids.

MS (m/z) APCI: 311 (M+H)⁺

The above compound was also synthesized by the following alternativemethod.

-   (1) To a solution of the compound (8-a) (15.0 g, 94.6 mmol) and    N-(tert-butoxycarbonyl)ethanolamine (30.50 g, 189.2 mmol) in DMF    (150 ml) was added portionwise potassium carbonate (26.15 g, 189.2    mmol), and the mixture was stirred at 50 to 60° C. for 4 hours,    cooled to room temperature, diluted with ethyl acetate, washed with    water and brine, and dried over sodium sulfate. After treating with    activated charcoal, the mixture was concentrated in vacuo and the    residue was crystallized from diisopropyl ether to give the compound    (11-a) (11.86 g, yield 44%).

MS (m/z) APCI: 284 (M+H)⁺

-   (2) To a solution of the above compound (1.08 g, 3.81 mmol) in ethyl    acetate (10 ml) was added 10% Pd—C (128 mg), and the mixture was    stirred vigorously at room temperature for 1 hour under hydrogen at    atmospheric pressure. The reaction mixture was filtered and the    filtrate was concentrated in vacuo to give the crude amine (1.09 g).-   (3) To a solution of the above amine in acetic acid (20 ml) were    added potassium acetate (1.87 g, 19.3 mmol) and potassium    thiocyanate (2.22 g, 22.8 mmol), and thereto was added dropwise    bromine (0.234 ml, 4.57 mmol) with cooling with an ice-water bath,    and then the mixture was stirred at room temperature for 1 hour. The    reaction mixture was diluted with ethyl acetate, washed with water,    an aqueous sodium sulfite solution and brine, and dried over sodium    sulfate. After treating with activated charcoal, the mixture was    concentrated in vacuo and the residue was crystallized from ethyl    acetate-hexane to give the above compound (516 mg, yield 44% through    the above 2 steps).

MS (m/z) APCI: 311 (M+H)⁺

Reference Example 12

The compound of REFERENCE EXAMPLE 10 was treated in the similar manneras REFERENCE EXAMPLE 11 to give the titled compound as colorlesscrystals.

MS (m/z) APCI: 325 (M+H)⁺

The above compound was also synthesized by the following alternativemethod.

-   (1) To a solution of the compound (8-a) (10.0 g, 63.08 mmol) and    N-(tert-butoxycarbonyl)-N-methylethanolamine (16.55 g, 94.6 mmol) in    dimethylsulfoxide (100 ml) was added portionwise potassium    tert-butoxide (10.62 g, 94.6 mmol) with cooling with an ice-water    bath. The mixture was stirred at room temperature for 50 minutes,    diluted with ethyl acetate, washed with water and brine, and dried    over sodium sulfate. After treating with activated charcoal, the    mixture was concentrated in vacuo to give the compound (12-a) (21.76    g).

MS (m/z) APCI: 298 (M+H)⁺

-   (2) The compound obtained in the above (1) was reacted in the    similar manner as the alternative method (2) of REFERENCE EXAMPLE 11    to give the crude amine.

MS (m/z) APCI: 268 (M+H)⁺

-   (3) The compound obtained in the above (2) was treated in the    similar manner as the alternative method (3) of REFERENCE EXAMPLE 11    to give the above compound.

MS (m/z) APCI: 325 (M+H)⁺

Reference Example 13

-   (1) Chlorosulfuric acid (80.0 g, 687 mmol) was ice-cooled, and    thereto was added 2-acetamidothiazole (20.00 g, 140.6 mmol) in    several portions, and the mixture was stirred at 100° C. overnight.    The reaction solution was cooled to room temperature, poured into    ice water and the mixture was extracted with diethyl ether. The    extract was washed with water and brine, dried over sodium sulfate,    and then concentrated in vacuo to give the crude product (13-b)    (9.41 g) as a yellow solid.-   (2) A mixture of a 2M aqueous dimethylamine solution (7.2 ml, 14.3    mmol) and pyridine (3 ml) was ice-cooled, and thereto was added the    compound (13-b) (1.50 g) in several portions. The mixture was    stirred at the same temperature for 15 minutes and at room    temperature overnight, concentrated in vacuo and the residue was    purified by silica gel chromatography (0 to 10% methanol-chloroform)    to give the crude product (13-c) (677 mg) as a yellow powder.-   (3) To the above compound (447 mg) was added 6N hydrochloric acid.    The mixture was stirred at 110° C. for 1 hour, cooled to room    temperature and concentrated in vacuo. To the residue were added    water and ammonia water were to be basic, and the precipitated    crystals were collected and dried to give the compound (13-d) (283    mg, yield 9% in 3 steps) as a yellow powder.

MS (APCI): 208 (M+H)⁺

Reference Example 14

Methylpiperazine was used in the similar manner as REFERENCE EXAMPLE 13to give the titled compound (yield 3% in 3 steps).

MS (APCI): 263 (M+H)⁺

Reference Example 15

-   (1) To a solution of    2-tert-butyloxycarbonylaminothiazole-5-carbaldehyde of REFERENCE    EXAMPLE 1 (4.37 g, 19.1 mmol) in THF (100 ml) were added    diethylphosphonoacetic acid ethyl ester (9.14 ml, 45.9 mmol) and    potassium tert-butoxide (5.16 g, 45.9 mmol) at room temperature, and    the mixture was stirred at the same temperature overnight, and then    heated to reflux for 5 hours. The reaction solution was cooled to    room temperature, and thereto was added water, and the mixture was    extracted with ethyl acetate. The organic layer was washed with    water and brine, dried over sodium sulfate, treated with activated    charcoal and then concentrated in vacuo, and the residue was    crystallized from ethyl acetate-hexane (1:5) to give the compound    (15-a) (4.13 g, yield 72%) as colorless crystals.

MS (APCI): 299 (M+H)⁺

-   (2) A mixture of the above compound (4.10 g, 13.74 mmol), 10% Pd/C    (5.0 g), ethyl acetate (50 ml) and acetic acid (50 ml) was stirred    vigorously at room temperature for 24 hours under hydrogen. The    reaction mixture was filtered and the filtrate was concentrated in    vacuo, and then chased with toluene several times to give the    compound (15-b) (4.05 g, yield 98%) as colorless crystals.

MS (APCI): 301 (M+H)⁺

-   (3) A solution of the above compound (4.03 g, 13.42 mmol) in a mixed    solvent of ethanol (20 ml), THF (40 ml) and water (20 ml) was    ice-cooled, and thereto was added dropwise a 2N sodium hydroxide    solution (16.1 ml, 32.2 mmol). The mixture was stirred at the same    temperature for 2 hours and then at room temperature for 3 hours,    poured into a mixture of aqueous citric acid solution and ethyl    acetate. The mixture was extracted with ethyl acetate, and the    extract was washed with water and brine, dried over sodium sulfate,    and concentrated in vacuo. The residue was crystallized from    diisopropyl ether to give the compound (15-c) (3.16 g, yield 86%) as    colorless crystals.

MS (ESI): 271 (M−H)⁻

-   (4) A solution of the above compound (589 mg, 2.16 mmol) and    1-hydroxybenzotriazole (584 mg, 4.33 mmol) in DMF (10 ml) was    ice-cooled, and thereto was added    N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide monohydrochloride    (1.04 g, 5.40 mmol), and the mixture was stirred at the same    temperature for 15 minutes and then at room temperature for 1 hour.    The reaction mixture was ice-cooled again, and thereto was added a    50% aqueous methylamine solution (5 ml). The mixture was stirred at    the same temperature for 10 minutes and at room temperature for 1    hour, poured into a mixture of ethyl acetate and brine, and the    mixture was extracted with ethyl acetate. The extract was washed    with a saturated aqueous sodium bicarbonate solution and brine,    dried over sodium sulfate, and concentrated in vacuo. The residue    was crystallized from ethyl acetate-hexane (1:10) to give the    compound (15-d) (597 mg, yield 92%) as colorless crystals.

MS (APCI): 300 (M+H)⁺

-   (5) To a solution of the above compound (202 mg, 0.675 mmol) in    formic acid (6 ml) was added a 4N solution of hydrogen chloride in    dioxane (2 ml, 8 mmol), and the mixture was stirred at room    temperature for 8 hours. To the mixture was added diethyl ether, and    the mixture was stirred at room temperature. The resulting crystals    were collected and washed with diethyl ether. To the crystals were    added a 4N solution of hydrogen chloride in dioxane (2 ml, 8 mmol)    and diethyl ether (10 ml), and the mixture was stirred further at    room temperature overnight. The crystals were collected and washed    with diethyl ether to give the compound (15-e) (175 mg) as colorless    crystals in quantitative yield.

MS (APCI): 200 (M+H)⁺

Reference Example 16

To the compound (15-e) of REFERENCE EXAMPLE 15 (173 mg, 0.734 mmol) wasadded ammonia water and brine, and the mixture was extracted withchloroform several times. The extract was dried over sodium sulfate andconcentrated in vacuo to give colorless crystals of the free compound(112 mg, yield 76%). A solution of the above compound (112 mg, 0.560mmol) in THF (3 ml) was ice-cooled, and thereto was added lithiumaluminum hydride (65 mg, 1.71 mmol), and the mixture was stirred at thesame temperature for 1 hour and at room temperature for 1 hour. To thereaction mixture was added ammonia water, and the mixture was stirred atroom temperature overnight. Thereto was added sodium sulfate, and thenthe mixture was filtered. The filtrate was concentrated in vacuo and theresulting residue was dissolved in ethyl acetate, and thereto were addeda 4N solution of hydrogen chloride in dioxane (0.5 ml, 1 mmol) anddiethyl ether, and the mixture was stirred at room temperature. Theprecipitate was collected and dried to give the titled compound (98 mg,yield 68%) as a colorless powder.

MS (APCI): 186 (M+H)⁺

Reference Example 17

A mixture of 2-amino-5-bromopyrazine (2.00 g, 11.5 mmol),cyclopropylboronic acid (1.28 g, 14.9 mmol), palladium acetate (258 mg,1.15 mmol), tricyclohexylphosphine (644 mg, 2.30 mmol) and tripotassiumphosphate (8.50 g, 40.23 mmol) in toluene-water (20:1) (53 ml) washeated to reflux for 18 hours. The mixture was cooled to roomtemperature, diluted with ethyl acetate, washed with water and brine,dried over magnesium sulfate, and then concentrated in vacuo. Theresulting residue was purified by silica gel column chromatography (50to 100% ethyl acetate-hexane) to give the titled compound (329 mg, yield21%) as a colorless powder.

MS (APCI): 136 (M+H)⁺

Reference Example 18

To a solution of the compound of REFERENCE EXAMPLE 8 (176 mg, 0.833mmol) and imidazole (188 mg, 2.76 mmol) in DMF (4 ml) was added dropwisea solution of tert-butyldimethylchlorosilane (188 mg, 1.25 mmol) in DMF(2 ml) under ice-cooling. The mixture was stirred at room temperatureovernight, diluted with ethyl acetate, washed with water and brine, andthen dried over sodium sulfate and concentrated in vacuo. Then, theresidue was purified by silica gel chromatography (40 to 70% ethylacetate-hexane) to give the titled compound (172 mg, yield 64%) ascolorless crystals.

MS (APCI): 326 (M+H)⁺

Reference Example 19

To a solution of 2-amino-5-bromothiazole hydrobromide (3.00 g, 11.5mmol) and 2-dimethylaminoethanethiol monohydrochloride (2.45 g, 17.31mmol) in water (15 ml)-ethanol (20 ml) was added a 1N aqueous sodiumhydroxide solution (23.5 ml, 23.5 mmol) at room temperature, and themixture was heated to reflux for 2 hours. The reaction solution wascooled to room temperature and concentrated in vacuo, and thereto wasadded a saturated aqueous sodium bicarbonate solution and sodiumchloride to saturation, and the mixture was extracted with ethyl acetateseveral times. The extract was dried over magnesium sulfate,concentrated in vacuo, and then the residue was purified by silica gelchromatography (NH-silica gel; methanol-chloroform=49:1 to 19:1) to givethe titled compound (2.10 g, yield 89%) as a brown solid.

MS (APCI): 204 (M+H)⁺

Reference Example 20

3-Mercapto-4-methyl-4H-1,2,4-triazole was used in the similar manner asREFERENCE EXAMPLE 19 to give the titled compound.

MS (APCI): 214 (M+H)⁺

Reference Example 21

2-Mercaptoethanol was used in the similar manner as REFERENCE EXAMPLE 19to give the titled compound.

MS (APCI): 177 (M+H)⁺

Reference Example 22

3-Mercaptopropanol was used in the similar manner as REFERENCE EXAMPLE19 to give the titled compound.

MS (APCI): 191 (M+H)⁺

Reference Example 23

To a mixture of 2-amino-5-bromothiazole hydrobromide (5.50 g, 21.2mmol), tert-butyl-N-(2-mercaptoethyl)carbamate (5.25 g, 29.6 mmol) andethanol (80 ml) was added 1,8-diazabicyclo[5.4.0]-7-undecene (7.73 g,50.8 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 7 hours. The reaction solution was concentrated invacuo, and the residue was diluted with ethyl acetate, and then washedwith water and brine, dried over magnesium sulfate and concentrated invacuo. Then, the residue was purified by silica gel chromatography(ethyl acetate-hexane=3:1) to give the titled compound 5.72 g, yield98%) as a colorless powder.

MS (APCI): 276 (M+H)⁺

Reference Example 24

-   (1) To a solution of the compound (24-a) synthesized according to    the known method (B. Koren et al., Heterocycles, 1987, 26(3) 689)    (1.00 g, 3.30 mmol) in DMF (40 ml) were added water (10 ml), sodium    formate (4.50 g, 66.2 mmol) and 10% Pd—C (200 mg), and the mixture    was stirred at 85° C. for 14 hours. After cooling to room    temperature, the reaction mixture was filtered and the filtrate was    concentrated in vacuo. To the residue was added water, and the    mixture was acidified with an aqueous citric acid solution, and then    the precipitated crystals were collected and dried to give the    compound (24-b) (720 mg, yield 97%) as a yellow powder.

MS (APCI): 225 (M+H)⁺

-   (2) To the above compound (700 mg, 3.12 mmol) was added a 10%    aqueous sodium hydroxide solution (20 ml), and the mixture was    stirred at 100° C. for 4.5 hours. The reaction solution was cooled    to room temperature, and then 10% hydrochloric acid was added to    neutralize and the precipitate was filtered off. The filtrate was    extracted with ethyl acetate and the extract was concentrated in    vacuo. The resulting residue was washed with diethyl ether to give    the compound (24-c) (228 mg, yield 48%) as a yellow powder.

MS (APCI): 153 (M+H)⁺

Reference Example 25

-   (1) A mixture of the compound (25-a) synthesized according to the    known method (B. Koren et al., Heterocycles, 1987, 26(3) 689) (482    mg, 2.09 mmol), 2,5-hexanedione (0.490 ml, 4.17 ml),    p-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol) and toluene    (5 ml) was heated to reflux for 3 hours with removing water by a    Dean-Stark apparatus. The reaction mixture was cooled to room    temperature, and then diluted with ethyl acetate and a small amount    of methanol, washed with a saturated aqueous sodium bicarbonate    solution and brine, and then dried over sodium sulfate. After    concentration in vacuo, the residue was purified by silica gel    chromatography (NH-silica gel; ethyl acetate-hexane=10:1, then ethyl    acetate) to give the compound (25-b) (598 mg, yield 93%) as pale    brown crystals.

MS (APCI): 309/311 (M+H)⁺

-   (2) A solution of the above compound (533 mg, 1.72 mmol) in methanol    (15 ml)-DMF (15 ml) was ice-cooled, and thereto was added sodium    methoxide (464 mg, 8.60 mmol). The mixture was stirred at room    temperature for 42 hours, diluted with ethyl acetate, washed with    water and brine, and then dried over sodium sulfate. After treatment    with activated charcoal, the mixture was concentrated in vacuo to    give the compound (25-c) (339 mg, yield 76%) as brown crystals.

MS (APCI): 261 (M+H)⁺

-   (3) A suspension of the above compound (330 mg, 1.27 mmol) in water    (30 ml) was ice-cooled, and thereto was added trifluoroacetic acid    (30 ml). The mixture was stirred at 60° C. for 4 hours, then cooled    to room temperature and concentrated in vacuo. The residue was    chased with toluene, and purified by silica gel chromatography    (NH-silica gel; methanol-chloroform=1:20 to 1:5). The resulting    crude crystals were washed with ethyl acetate-hexane (1:3) to give    the compound (25-d) (154 mg, yield 67%) as reddish brown crystals.

MS (APCI): 183 (M+H)⁺

Reference Example 26

To a solution of potassium thiocyanate (6.10 g, 63 mmol) in acetic acid(25 ml) was added 5-aminopyrimidine (1.00 g, 10.5 mmol), and thereto wasadded dropwise a solution of bromine (1.08 ml, 21.0 mmol) in acetic acid(3 ml) with cooling by ice bath. The mixture was stirred at roomtemperature for 3 days and concentrated in vacuo. The residue wasneutralized with a saturated aqueous sodium bicarbonate solution andthen concentrated in vacuo. To the residue were added chloroform andTHF, and the mixture was dried over magnesium sulfate and filtered. Thefiltrate was concentrated in vacuo and the resulting residue waspurified by silica gel chromatography (methanol-chloroform=1:20 to 1:10)to give the titled compound (287 mg, yield 18%) as a yellow powder.

MS (APCI): 153 (M+H)⁺

Reference Example 27

-   (1) A suspension of the compound (27-a) synthesized according to the    known method (T. Takahashi et al., Chemical & Pharmaceutical    Bulletin, 1958, 6, 334) (1.00 g, 4.62 mmol) in methanol (20 ml) was    cooled to −40° C., and thereto was added a solution of 28% sodium    methoxide in methanol (0.305 ml, 4.85 mmol), and the mixture was    stirred at the same temperature for 6 hours. Water was added, and    the mixture was extracted with ethyl acetate. The organic layer was    dried over sodium sulfate and concentrated in vacuo. The residue was    purified by silica gel chromatography (15 to 35% ethyl    acetate-hexane) to give the compound (27-b) (194 mg, yield 20%) as a    yellow powder.-   (2) To a solution of the above compound (663 mg, 3.12 mmol) in    acetic acid (6 ml) was added iron powder (678 mg, 12.2 mmol) at room    temperature, and the mixture was stirred at 60° C. for 4 hours.    After cooling to room temperature, the mixture was diluted with    ethyl acetate, and filtered through Celite. The filtrate was    concentrated and then the residue was diluted with ethyl acetate,    and thereto was added a saturated aqueous sodium bicarbonate    solution, and then the insoluble was filtered off. The filtrate was    extracted with ethyl acetate, and the organic layer was dried over    sodium sulfate and concentrated in vacuo. The residue was purified    by silica gel chromatography (ethyl acetate) to give the compound    (27-c) (231 mg, yield 41%) as a yellow powder.

MS (APCI): 183 (M+H)⁺

Reference Example 28

-   (1) A mixture of the compound (28-a) (3.05 g, 16.4 mmol),    2,5-hexanedione (3.85 ml, 32.9 mmol), p-toluenesulfonic acid    monohydrate (313 mg, 1.64 mmol) in toluene (30 ml) was heated to    reflux for 6 hours with removing water by a Dean-Stark apparatus.    The reaction mixture was cooled to room temperature, and then    diluted with ethyl acetate, washed with a saturated aqueous sodium    bicarbonate solution and brine, and dried over sodium sulfate. After    concentration in vacuo, the residue was purified by silica gel    chromatography (ethyl acetate-hexane=1:10) to give the compound    (28-b) (3.84 g, yield 89%) as pale brown crystals.

MS (APCI): 264/266 (M+H)⁺

-   (2) To a suspension of the above compound (600 mg, 2.27 mmol),    bis(dibenzylideneacetone)palladium (131 mg, 0.227 mmol),    2-dicyclohexylphosphono-2′-(N,N′-dimethylamino)biphenyl (89 mg,    0.226 mmol) and sodium tert-butoxide (437 mg, 4.55 mmol) in toluene    (10 ml) was added a 2M solution of dimethylamine in THF (6.81 ml,    13.6 mmol) at room temperature under argon, and the mixture was    stirred at the same temperature for 5 days. Water was added, and the    mixture was extracted with ethyl acetate. The organic layer was    washed with water and brine, dried over sodium sulfate and then    concentrated in vacuo. The residue was purified by silica gel    chromatography (10 to 35% ethyl acetate-hexane) to give the compound    (28-c) (419 mg, yield 68%) as brown crystals.

MS (APCI): 273 (M+H)⁺

-   (3) A suspension of the above compound (410 mg, 1.51 mmol) in water    (30 ml) was ice-cooled, and thereto was added trifluoroacetic acid    (30 ml). The mixture was stirred at 50° C. for 1 hour, cooled to    room temperature, and then concentrated in vacuo. The residue was    extracted with ethyl acetate. The organic layer was washed with a    saturated aqueous sodium bicarbonate solution and brine, dried over    sodium sulfate, and then treated with activated charcoal. After    concentration in vacuo, the residue was crystallized from ethyl    acetate-hexane (3:1) to give the compound (28-d) (194 mg, yield 66%)    as a colorless powder.

MS (APCI): 195 (M+H)⁺

Reference Example 29

A mixture of 2-amino-5-bromopyrazine (2.61 g, 15.0 mmol),tert-butylcarbamate (2.11 g, 18.0 mmol), copper (I) iodide (290 mg, 1.50mmol), N,N′-dimethylethylenediamine (260 mg, 3.00 mmol), potassiumcarbonate (4.15 g, 30.0 mmol) in dioxane (80 ml) was heated to refluxfor 16 hours. The mixture was cooled to room temperature, poured intowater and extracted with ethyl acetate. The extract was filtered throughCelite and the filtrate was concentrated in vacuo, and the resultingresidue was purified by silica gel chromatography (30 to 80% ethylacetate-hexane) to give the titled compound (yield 18%) as a colorlesspowder.

MS (APCI): 211 (M+H)⁺

Reference Example 30

-   (1) A suspension of the compound (28-b) (1.86 g, 7.05 mmol),    tert-butyldimethyl(tributylstannylmethoxy)silane (6.14 g, 14.1 mmol)    and dichlorobis(triphenylphosphine)palladium (495 mg, 0.701 mmol) in    dioxane (20 ml) was heated to reflux for 41 hours under argon. The    reaction mixture was cooled to room temperature, and thereto was    added activated charcoal. The mixture was filtered, and the filtrate    was concentrated in vacuo. To the resulting residue was dissolved    ethyl acetate, washed with a saturated aqueous sodium bicarbonate    solution and brine, dried over sodium sulfate and concentrated in    vacuo to give the compound (30-a) (10.44 g) as a yellow oil.-   (2) A mixture of the above compound (10.4 g) in water (60 ml) was    ice-cooled, and thereto was added trifluoroacetic acid (60 ml). The    mixture was stirred at 50° C. for 1 hour, cooled to room    temperature, and then concentrated in vacuo. To the resulting    residue was added a saturated aqueous sodium bicarbonate solution,    and the mixture was saturated with sodium chloride and extracted    with ethyl acetate. The extract was dried over sodium sulfate and    then concentrated in vacuo, and the residue was chased with toluene    and then crystallized from a mixed solvent of ethyl acetate-hexane    to give the compound (30-b) (1.10 g) as a brown powder.-   (3) To a solution of the above compound (1.10 g) and imidazole (1.54    g, 22.6 mmol) in DMF (30 ml) was added    tert-butyldimethylchlorosilane (1.70 g, 11.3 mmol) under    ice-cooling. The mixture was stirred at room temperature for 1 hour,    diluted with ethyl acetate, washed with a saturated aqueous sodium    bicarbonate solution and brine, and dried over sodium sulfate. After    concentration in vacuo, the resulting residue was purified by silica    gel column chromatography (NH-silica gel; 60 to 100% ethyl    acetate-hexane) to give the compound (30-c) (354 mg, yield 16% in 3    steps) as pale yellow crystals.

MS (APCI): 296 (M+H)⁺

Reference Example 31

A mixture of 2-amino-5-iodopyridine (1.00 g, 4.55 mmol), methylthioglycolate (0.482 g, 4.55 mmol),tris(dibenzylideneacetone)-dipalladium (208 mg, 0.227 mmol),bis(2-diphenylphosphinophenyl)-ether (245 mg, 0.455 mmol) and potassiumtert-butoxide (561 mg, 5.00 mmol) in toluene (20 ml) was stirred at 100°C. for 3 hours under argon. The reaction mixture was cooled to roomtemperature and filtered through Celite, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography (NH-silica gel, 0 to 3% methanol-chloroform) to give thetitled compound (268 mg, yield 30%) as a pale yellow solid.

MS (APCI): 199 (M+H)⁺

Reference Example 32

-   (1) The compound (32-a), (S)-1-acetyl-2-methylpiperazine    hydrochloride and diisopropylethylamine were treated in the similar    manner as EXAMPLE 2 to give the compound (32-b).

MS (m/z) APCI: 349 (M+H)⁺

-   (2) The compound obtained in the above (1) was treated in the    similar manner as EXAMPLE 138-(2) to give the compound (32-c).

MS (m/z) APCI: 249 (M+H)⁺

Reference Example 33

-   (1) A mixture of the compound (28-b) of REFERENCE EXAMPLE 28 (2.00    g, 7.58 mmol) and N,N,N′-trimethylethylenediamine (7.74 g, 75.8    mmol) was stirred at 125° C. for 15 hours. The reaction mixture was    cooled to room temperature and concentrated in vacuo. To the residue    was added ethyl acetate and the insoluble materials were filtered    off. The filtrate was concentrated in vacuo and the residue was    purified by silica gel column chromatography (NH-silica gel; 15 to    35% ethyl acetate-hexane) to give the compound (33-a) (2.33 g, yield    93%).

MS (m/z) APCI: 330 (M+H)⁺

-   (2) To a solution of the above compound (530 mg, 1.61 mmol) in    methanol (2 ml) was added 10% hydrochloric acid (3.3 ml), and the    mixture was stirred at 60° C. for 19 hours, cooled to room    temperature, neutralized with sodium bicarbonate and concentrated in    vacuo. To the residue was added chloroform, and the mixture was    dried over magnesium sulfate and filtered, and the filtrate was    concentrated in vacuo. The resulting crude crystals were washed with    ethyl acetate-diethyl ether to give the compound (33-b) (201 mg,    yield 50%).

MS (m/z) APCI: 252 (M+H)⁺

Corresponding starting compounds were treated in the similar manner asthe above REFERENCE EXAMPLE 33, REFERENCE EXAMPLE 11-(2) or REFERENCEEXAMPLE 18 or an appropriate combination thereof to give the followingcompounds.

REFERENCE EXAMPLE No. No Structure MS (m/z) 33 1

338 APCI[M + H]⁺ 33 2

238 APCI[M + H]⁺ 33 3

339 APCI[M + H]⁺ 33 4

325 APCI[M + H]⁺

Reference Example 34

-   (1) A mixture of the compound (28-b) (500 mg, 1.90 mmol),    tert-butylcarbamate (333 mg, 2.84 mmol), cesium carbonate (1235 mg,    3.79 mmol), palladium (II) acetate (21.3 mg, 0.095 mmol),    4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87.7 mg, 0.152    mmol) and dioxane (5 ml) was stirred at 100° C. for 15 hours under    argon. The reaction mixture was cooled to room temperature, and    thereto was added water, and the mixture was extracted with ethyl    acetate. The extract was concentrated in vacuo. The residue was    purified by silica gel chromatography (5 to 15% ethyl    acetate-hexane) to give the compound (34-a) (727 mg,    quantitatively).

MS (m/z) APCI: 345 (M+H)⁺

-   (2) A solution of the compound obtained in the above (1) (633 mg,    1.84 mmol) in DMF (4 ml) was ice-cooled, and thereto were added    sequentially methyl iodide (0.126 ml, 2.02 mmol) and 60% sodium    hydride (110 mg, 2.76 mmol), and the mixture was stirred at the same    temperature for 10 minutes, poured into water and extracted with    ethyl acetate. The extract was concentrated in vacuo, and the    residue was purified by silica gel chromatography (NH-silica gel, 0    to 10% ethyl acetate-hexane) to give the compound (34-b) (556 mg,    yield 84%).

MS (m/z) APCI: 359 (M+H)⁺

-   (3) A mixture of the compound obtained in the above (2) (556 mg,    1.55 mmol), 10% hydrochloric acid (7 ml) and methanol (6 ml) was    stirred at 75° C. for 23 hours. The reaction mixture was cooled to    room temperature, and thereto was added a saturated aqueous sodium    bicarbonate solution and the mixture was extracted with chloroform.    The extract was concentrated in vacuo to give the compound (34-c)    (300 mg, quantitatively).

MS (m/z) APCI: 181 (M+H)⁺

Reference Example 35

The compound (34-a) of REFERENCE EXAMPLE 34 was treated in the similarmanner as the method of REFERENCE EXAMPLE 34-(3) to give the titledcompound.

MS (m/z) APCI: 167 (M+H)⁺

Reference Example 36

Corresponding starting compounds were reacted in the similar manner asthe alternative method of REFERENCE EXAMPLE 11 or REFERENCE EXAMPLE 12to give the following compounds.

REFERENCE EXAMPLE No. No Structure MS (m/z) 36 1

351 APCI[M + H]⁺ 36 2

337 APCI[M + H]⁺ 36 3

337 APCI[M + H]⁺ 36 4

323 APCI[M + H]⁺ 36 5

339 APCI[M + H]⁺ 36 6

339 APCI[M + H]⁺

Reference Example 37

To a suspension of 2-amino-4-chloromethylthiazole hydrochloride (2.00 g,10.8 mmol) in dioxane (15 ml) was added N-methylpiperazine (12 ml, 108mmol), and the mixture was stirred at room temperature for 110 hours. Tothe reaction mixture was added a saturated aqueous sodium bicarbonatesolution (5 ml) and the organic layer was separated by Chem Elut 1010®(manufactured by VARIAN) and the column was further eluted withchloroform. The eluate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (NH-silica gel; 2%methanol-chloroform) to give the above compound (1.18 g, yield 52%).

MS (m/z) APCI: 213 (M+H)⁺

Reference Example 38

A corresponding starting compound was treated in the similar manner asREFERENCE EXAMPLE 38 to give the above compound.

MS (m/z) APCI: 227 (M+H)⁺

Reference Example 39

To a solution of the compound of REFERENCE EXAMPLE 1 (10.00 g, 60.7mmol), (S)-2-methyl-1-acetylpiperazine hydrochloride (15.0 g, 85.0 mmol)and diisopropylethylamine (26.0 ml, 149 mmol) in chloroform (300 ml) wasadded sodium triacetoxyborohydride (18.0 g, 85.0 mmol), and the mixturewas stirred at room temperature for 17 hours. To the reaction mixturewas added a saturated aqueous sodium bicarbonate solution, and themixture was extracted with chloroform. The extract was dried overmagnesium sulfate. After concentration in vacuo the residue was purifiedby silica gel column chromatography (6% methanol-chloroform) andcrystallized from ethyl acetate-diethyl ether to give the above compound(10.99 g, yield 71%).

MS (m/z) APCI: 255 (M+H)⁺

Reference Example 40

A corresponding starting compound was treated in the similar manner asEXAMPLE 39 to give the above compound.

MS (m/z) APCI: 213 (M+H)⁺

Reference Example 41

A solution of the compound of REFERENCE EXAMPLE 29 (1.61 g, 7.70 mmol)in DMF (16 ml) was ice-cooled, and thereto was added potassiumtert-butoxide (945 mg, 8.42 mmol). The mixture was stirred at roomtemperature for 10 minutes, ice-cooled again and thereto was addedmethyl iodide (572 ml, 9.19 mmol). The mixture was stirred at roomtemperature for 6 hours. To the reaction mixture was added water, andthe mixture was extracted with chloroform. The extract was washedsequentially with water and brine, dried over sodium sulfate and thenconcentrated in vacuo. The residue was purified by column chromatography(NH-silica gel, 10 to 35% ethyl acetate-hexane) to give the abovecompound (1.51 g, yield 88%).

MS (m/z) APCI: 225 (M+H)⁺

Reference Example 42

A mixture of 2-amino-5-bromopyrazine (5.00 g, 28.74 mmol),2-pyrrolidinone (10.90 ml, 143.7 mmol), cuprous iodide (1.10 g, 5.75mmol), (1R,2R)-(−)-1,2-diaminocyclohexane (1.38 ml, 11.50 mmol),potassium carbonate (7.94 g, 57.5 mmol) and dioxane (86 ml) was stirredat 120° C. for 17 hours under argon. The reaction mixture was cooled toroom temperature and thereto was added ethyl acetate-methanol (10:1),and the mixture was filtered through Celite. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (5% methanol-chloroform) and crystallized from diethylether to give the above compound (2.77 g, yield 54%).

MS (m/z) APCI: 179 (M+H)⁺

Reference Example 43

1-tert-Butoxycarbonyl-4-acetylthiopiperidine (4.60 g, 17.69 mmol) and2-amino-5-bromothiazole hydrobromide were reacted in the similar manneras REFERENCE EXAMPLE 19 to give the above compound.

MS (m/z) APCI: 316 (M+H)⁺

Reference Example 44

To 2-methoxyethanol (55 ml) were added sequentially 60% sodium hydride(1.83 g, 45.8 mmol), 2-amino-5-bromopyrazine (7.00 g, 40.23 mmol) andcopper powder (2.91 g, 53.9 mmol) under ice-cooling, and the mixture wasstirred at 160° C. for 20 hours in a sealed tube. The reaction mixturewas cooled to room temperature, and thereto were added water, ammoniawater and ethyl acetate, and the mixture was stirred and then filteredthrough Celite. The filtrate was extracted with ethyl acetate. Theextract was dried over sodium sulfate, and after concentration in vacuothe residue was purified by silica gel column chromatography (40% ethylacetate-hexane) to give the titled compound (2.74 g, yield 40%).

MS (m/z) APCI: 170 (M+H)⁺

Corresponding starting compounds were treated in the similar manner asthe above REFERENCE EXAMPLE 44, REFERENCE EXAMPLE 11-(2) or REFERENCEEXAMPLE 18 or an appropriate combination thereof to give the followingcompounds.

REFERENCE EXAMPLE No. No Structure MS (m/z) 44 1

270 APCI[M + H]⁺ 44 2

154 APCI[M + H]⁺

Reference Example 45

-   (1) A solution of (S)-1-acetyl-2-methylpiperazine hydrochloride    (0.800 g, 4.50 mmol) and diisopropylethylamine (1.81 ml, 10.4 mmol)    in DMF (10 ml) was ice-cooled, and thereto was added the compound    (45-a). The mixture was stirred at the same temperature for 3 hours,    diluted with water, extracted with ethyl acetate and the extract was    concentrated in vacuo. The residue was purified by silica gel column    chromatography (ethyl acetate) to give the compound (45-b) (0.930 g,    yield 76%).    MS (m/z) APCI: 350 (M+H)⁺-   (2) The compound obtained in the above (1) was reacted in the    similar manner as EXAMPLE 138-(2) to give the compound (45-c).    MS (m/z) APCI: 250 (M+H)⁺

Reference Example 46

Corresponding starting compounds were treated with2-amino-6-hydroxybenzothiazole in the similar manner as REFERENCEEXAMPLE 5 to give the following compounds.

REFERENCE EXAMPLE No. No Structure MS (m/z) 46 1

325 APCI[M + H]⁺ 46 2

324 APCI[M + H]⁺

Reference Example 47

-   (1) A solution of the compound (47-a) (1.50 g, 5.63 mmol) and    N,N-dimethylethanolamine (535 mg, 6.00 mmol) in THF (20 ml) was    ice-cooled, and thereto were added triphenylphosphine (1.57 g, 6.00    mmol) and diethyl azodicarboxylate (1.04 g, 6.00 mmol), and the    mixture was stirred at the same temperature overnight. To the    reaction mixture were added ethyl acetate and diluted hydrochloric    acid. The aqueous layer was separated and basified with an aqueous    sodium hydroxide solution. After extraction with ethyl acetate, the    extract was dried over sodium sulfate and concentrated in vacuo, and    the residue was purified by silica gel chromatography (40 to 60%    acetone-chloroform) and then washed with diisopropyl ether to give    the compound (47-b) (606 mg, yield 32%) as a colorless powder.-   (2) To a solution of the compound (47-b) obtained in the above (1)    (337 mg, 1.0 mmol) in methanol (5 ml) was added a 4 M hydrogen    chloride solution in dioxane (2.5 ml) at room temperature, and the    mixture was stirred at the same temperature overnight. The reaction    mixture was concentrated in vacuo and the residue was washed with    diethyl ether to give the compound (47-c) (302 mg, yield 97%) as a    colorless powder.    MS (m/z) APCI: 238 (M+H)⁺

INDUSTRIAL APPLICABILITY

The compound of the present invention or a pharmaceutically acceptablesalt thereof can provide an agent for preventing or treating diseasesinvolving glucokinase because of having an excellent glucokinaseactivation effect.

Also, the method for preparing 5-substituted 2-aminothiazole compound ofthe present invention and a salt thereof is industrially advantageous.

1. A compound of the general formula:

wherein R^(5A) is a group of

or a pharmaceutically acceptable salt thereof.
 2. A method for treatingdiabetes or a complication associated with diabetes, which comprises:administering an effective dose of a compound of claim 1 or apharmaceutically acceptable salt thereof to a patient in need thereof,wherein said complication associated with diabetes is one or morecomplication selected from the group consisting of retinopathy,nephropathy, ischemic heart disease, arteriosclerosis and obesity.
 3. Apharmaceutical composition comprising an effective amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof as an activeingredient.